Treating Ulcerative Colitis

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Treating Ulcerative Colitis

• Robert Theobald III, D.O.
• Vein Associates, P.A.

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Introduction

• Ulcerative colitis is a chronic inflammatory
  disease of unknown etiology
• Primarily affects the colon and rectum
• Lesions are characterized by superficial
  infiltration of the bowel wall by inflammatory
  white cells
• Results in mucosal ulcerations and crypt abscesses

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History

• Ulcerative colitis was first recognized as a
  distinct disease in England during the late 19th
  century
• In the absence of effective drug therapy,
  surgical intervention was the approach, creating
  a lower bowel ostomy
• Antiseptic solutions were infused through the
  ostomy to achieve remission

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Epidemiology

• The incidence of UC occurs in distinct patterns
• Northern countries such as United Kingdom,
  Norway, Sweden, and the United States have the
  highest rates of the disease
• A northern California study revealed that of 10.9
  per 100,000 people have UC

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Epidemiology

• A study from Baltimore suggested that the
  incidence of UC is greater in caucasians than in
  African Americans31
• Friedman et al stated that the incidence of UC is
  4-fold higher in Jewish decent than in other
  ethnic groups
• Smoking is the most extensively studied factor
  associated with IBD. Smokers have a decreased
  risk for developing UC. Increased risk of
  Crohns

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Epidemiology
Ulcerative Colitis
6 to 12 per 100,000
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Clinically

• Patient presents with bloody diarrhea, anorexia,
  abdominal pain, fever, mucous, and weight loss
• About 5 of patients have only one acute UC
  episode and never reoccurs
• 20-25 of patients that develop severe UC do not
  respond to pharmacotherapy

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Clinical Presentation

• In a study by Rao et al the prevalence of
  symptoms and stool patterns was assessed
• 96 patients with UC were subdivided according to
  the extent and activity of the disease
• All symptoms were significantly more common in
  patients with active colitis

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Clinical Presentation Symptoms
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Colitis Activity Assessment
FULMINANT
SEVERE
MILD
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Diagnosis

• The diagnosis of UC is based on the clinical
  picture, stool examination, colonoscopic
  appearance, and histologic assessment of biopsied
  specimens
• The differential diagnosis includes infectious,
  chemical, IBS, ischemia, and miscellaneous

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Diagnosis
Ulcerative Colitis
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Disease Distribution at Presentation

• 1,116 patients with a confirmed diagnosis of UC
  were studied at the Cleveland Clinic Foundation
• The mean age at diagnosis was 32 years
• Early complications included colonic hemorrhage
  (16.7) and toxic colitis (12.7)
• Complications were highest among patients with
  pancolitis
• Surgery was required for 37.6

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Disease Distribution at Presentation
n1116
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Current Pharmacotherapy

• Because no cure for UC has been found, treatment
  of the disease consists of long-term
  pharmacotherapy
• Directed at controlling the symptoms of the
  disease
• The ultimate goal is to achieve remission and
  avoid surgery

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Sulfasalazine

• Became available in the 1940s when Svatz et al
  discovered that sulfasalazine, originally used to
  treat RA, was also noted to reduce colonic
  mucosal inflammation and bloody diarrhea

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Sulfasalazine

• Is indicated for the treatment of mild to
  moderate UC, as adjunctive therapy in severe
  cases, and for prolongation of remission
• It is a prodrug comprised of mesalamine and
  sulfapyridine joined by a diazo bond
• About 1/3 of the dose is absorbed in the small
  intestine

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Sulfasalazine

• The remainder of the dose reaches the colon
  without being absorbed
• Bacterial enzymes in the colon split the diazo
  bond, liberating the two components
• About 1/3 of the mesalamine released in the colon
  is absorbed and excreted in the urine while the
  remaining mesalamine is unabsorbed and is
  excreted in the feces

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Sulfasalazine

• The efficacy of sulfasalazine is dose-dependent
• Doses greater than 4.0 g/d and serum
  sulfapyridine concentrations above 50 ug/ml are
  associated with a greater risk of toxicity
• In a review by Taffet et al, up to 1/3 of
  patients given sulfasalazine experience some
  degree of intolerance to the drug

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Sulfasalazine

• Adverse events of sulfasalazine are of two types
  dose-related or hypersensitivity
• The first group includes nausea, vomiting,
  abdominal discomfort, anorexia, and headache.
• Less common include hemolytic anemia,
  reticulocytosis, and methemoglobinemia

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Sulfasalazine

• The second group are non-dose dependent
• They include exfoliative dermatitis, aplastic
  anemia, hepatitis, pancreatitis, pneumonitis,
  autoimmune hemolysis, pericarditis, nephrotic
  syndrome, and severe exacerbation of symptoms of
  colitis

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Sulfa-Free Oral Mesalamine

• Studies have shown that mesalamine is the
  principal therapeutically active component of
  sulfasalazine, while sulfapyridine is the carrier
• Recognition that sulfapyridine is associated with
  dose-related adverse events led to efforts to
  develop sulfa-free products
• These include Asacol (mesalamine), Dipentum
  (olsalazine), Pentasa (mesalamine), and Colazal
  (balsalazide)

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Asacol (mesalamine)

• Asacol tablets were introduced to the US in 1992
• Unlike sulfasalazine, olsalazine, and
  balsalazine, Asacol is not a prodrug
• It contains a core of 400 mg of mesalamine coated
  with a pH-sensitive acrylic polymer call
  Eudragit-S which delays release of mesalamine
  until the tablet reaches an environment of pH of
  7 or above
• The coating typically dissolves in the terminal
  ileum or colon

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Asacol (mesalamine)

• Asacol is indicated for the treatment of mildly
  to moderately active UC and the maintenance of
  remission
• The usual dose is two 400-mg tablets to be taken
  three times a day for a total daily dose of 2.4 g
  for a duration of 6 weeks
• For maintenance the recommended dose is 1.6 g
  daily, in divided doses

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Pentasa (mesalamine)

• Pentasa has been marketed in the US since 1993
• Pentasa is also not a prodrug
• Unlike Asacol, the delivery system is made up of
  mesalamine microspheres
• It is moisture activated, thus the capsules
  disintegrate in the stomach, dispersing
  controlled-release microspheres into the small
  bowel and throughout the rest of the colon

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Pentasa (mesalamine)

• Pentasa is indicated for the induction of
  remission and for the treatment of mildly to
  moderately active UC
• The recommended dose is four 250-mg capsules four
  times a day for a total daily dose of 4.0 g
• Treatment duration is up to 8 weeks
• Is not indicated for maintenance UC

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Dipentum (olsalazine)

• Dipentum was introduced to the US in 1990 and
  contains 250-mg of olsalazine sodium
• It is a prodrug consisting of two molecules of
  mesalamine joined by a diazo bond which is
  cleaved by bacterial action in the colon

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Dipentum (olsalazine)

• Dipentum is indicated for maintenance of
  remission of UC in patients intolerant to
  sulfasalazine
• The usual dose is two 250-mg capsules twice a day
  for a total daily dose of 1.0 g
• Dipentum is not indicated for the treatment of
  acute ulcerative colitis

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Colazal (balsalazide)

• Colazal was introduced to the US in 2000 and
  contains 750-mg of balsalazide sodium
• It is a prodrug and is delivered intact to the
  colon where it is cleaved by bacterial
  azoreduction to release mesalamine
• 70 of patients intolerant of sulfasalazine are
  able to tolerate balsalazide

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Colazal (balsalazide)

• The recommended dose of 6.75 g/day contains 2.4 g
  of mesalamine
• It is indicated for the treatment of mildly to
  moderately active ulcerative colitis
• The safety and effectiveness of Colazal beyond 12
  weeks has not been established
• Is not indicated for the maintenance of UC

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Oral 5-ASA Release Sites
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Fallingborg Study

• pH of the gut lumen was measured in 39 people
  with UC using a pH-sensitive, radiotransmitting
  capsule
• The location of the capsule was determined by
  X-ray
• The pH was 5.7 in the cecum, but rose to 6.6 in
  the rectum

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Fallingborg Study

• The low pH in the cecum is thought to be caused
  by bacterial fermentation of non-absorbed
  carbohydrates
• In 17 of the subjects, the pH decreased by
  0.1-0.8 units while leaving the terminal ileum
  and entering the cecum
• In the cecum the pH dropped between 0.5-2.5 pH
  units to a median value of 5.7

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Fallingborg Study

• The pH levels ascending and transverse colon had
  a median average of 5.6 and 5.7 respectively
• The pH in the descending, the sigmoid, and the
  rectum average 6.6
• The median fecal pH was 6.5

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Variance in Colonic pH
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Steroids

• Corticosteroids, such as prednisone,
  methylprednisolone, and budesonide have been used
  to reduce inflammation in patients who do not
  respond to 5-ASA meds
• Can be given orally, intravenously, an enema, or
  suppository
• See improvement within days
• Are a short term control of flare-up

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Steroids

• Long term use increase likelihood of side effects
• Weight gain
• Acne
• Facial hair
• HTN
• Osteoporosis
• Diabetes
• Mood swings
• Risk of infection

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Immunomodulators

• Azathioprine (Imuran) and 6-mercaptopurine (6-MP)
• Used to maintain remission of UC and decrease the
  need for steroids
• Can take 3-6 months to produce effectiveness
• Side effects include nausea, vomiting, diarrhea,
  pancreatitis, liver disease, and bone marrow
  disfunction
• Need CBC and LFT every few months

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Sequential Therapy
Induction of Acute Disease
Rectosigmoid Disease
Extensive Disease
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New Therapy for Treatment of UC

• Tumor necrosis factor-alpha is a chemical
  produced by the body
• It is responsible for recruiting immune cells to
  different tissue where they cause inflammation,
  swelling, pain, warmth, and erythema
• High concentrations of TNF have been found in a
  variety of infections and inflammatory diseases
  such as UC

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Remicade (infliximab) to Treat Ulcerative Colitis

• Remicade is an anti-TNF drug
• Remicade is a monoclonal antibody that is formed
  by combining portions of human and murine
  antibody molecules
• It targets and neutralizes TNF, thus decreasing
  the inflammatory response

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Remicade (infliximab) to Treat Ulcerative Colitis

• In a retrospective study by Sands et al, 16
  patients with severe UC received a single 5-mg/kg
  infusion of remicade
• Clinical, endoscopic, and histological
  improvements were observed in 88 (14/16) of
  patients after initial treatment
• 5 months later, 38 (6/16) of the patients
  received a second infusion to maintain remission

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Remicade (infliximab) to Treat Ulcerative Colitis

• Surgery was avoided in 6/7 patients who were
  previous surgical candidates
• Clinical remission was maintained in 14/16
  patients for at least six months and in 4/16 for
  at least ten months
• Most of the patients were completely withdrawn
  from corticosteroid therapy

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Remicade (infliximab) to Treat Ulcerative Colitis

• In a second study, 11 patients with severe UC
  were randomized to either receive a single
  infusion of remicade or a placebo
• Of the 8 patients receiving the remicade, 4
  experienced a clinical response at 2 weeks
• Of the 3 patients receiving the placebo, all 3
  experienced no response

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Remicade (infliximab) to Treat Ulcerative Colitis

• Some of the most common symptoms, as with any
  drug, are headaches, nausea, vomiting, URI,
  dizziness, and rashes
• More serious complications include TB, pneumonia,
  sepsis, herpes zoster, leukemia, and lymphoma
• Additionally, some people were noted to become
  ANA and anti-double-stranded DNA positive

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Natural Remedies

• www.copingwithcolitis
• Seasilver 100 plant-based nutritional
  supplement 1-STAR
• Cats Claw Helps normalize the balance of
  beneficial microbes and reverse conditions of
  intestinal inflammation 5-STAR

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Questions?