Therapeutics/Ulcerative Colitis

Case

A 20-year-old male with no past medical history presents with 2 months of rectal bleeding, increasingly loose stools associated with urgency, and nocturnal bowel movements. Additionally, he describes intermittent, subjective, low-grade fevers, a 4.5 kg (10 pound) weight loss and bilateral pain and swelling in his knees. He smokes a pack of cigarettes daily and his maternal uncle has ulcerative colitis. On physical exam his abdomen is soft and non-distended with mild, diffuse tenderness to palpation. Perianal exam reveals external skin tags with no fissure or fistula. Laboratory studies reveal mild leukocytosis with a left shift and microcytic anemia. Colonoscopy shows patchy inflammation of the entire colon with a normal terminal ileum.

Therapeutics

The goals of therapy in Inflammatory bowel disease patients are to induce and maintain symptomatic remission, and prevent complications of disease and therapies. The intensity of therapy used to induce remission generally dictates the effective maintenance strategies.

Current approaches to therapy include sequential induction to maintenance treatment according to the severity of symptoms at diagnosis. Patients with mild ulcerative colitis (ambulatory patients with symptoms that do not have a major impact on quality of life and less than four to six bowel movements daily and without extraintestinal manifestations) can be treated with aminosalicylates.

Table Differential diagnosis of inflammatory bowel disease

If symptoms completely resolve on aminosalicylates, maintenance therapy with an ami-nosalicylate should be continued. Patients with moderate to severe symptoms or those who fail to respond to aminosalicylates are induced with corticosteroids or an anti-tumor necrosis factor biologic. Steroid-induction more often requires maintenance therapy with a thiopurine, or anti-tumor necrosis factor biologic, in particular if the colitis is not controlled by high-dose (e.g., 4-5g/day) mesalamine. Patients who fail steroid-induction or maintenance therapy with a thiopurine typically respond to anti-tumor necrosis factor induction and regularly scheduled maintenance therapy.

5-Aminosalicylates

Aminosalicylates (mesalamine, sulfasalazine, olsalazine, balsalazide) are first-line therapies for induction and remission of mild to moderate ulcerative colitis and, despite conflicting evidence, are often used early in the treatment algorithm for Crohn disease. Several oral and rectally administered preparations are available, each employing unique mechanisms for delivering 5-ASA (mesalamine) to the colon. Specific delivery mechanisms include linking 5-ASA to a carrier molecule via an azo bond that is cleaved by colonic bacteria, use of moisture-dependent time-release granules that deliver 5-ASA throughout the bowel, or pH-dependent coatings that release 5-ASA in the terminal ileum and colon. Mesalamine delivered topically, as an enema foam or suppository, is highly effective to treat distal colitis. Side effects are rare with this class of medications, but may include interstitial nephritis, pancreatitis, hepatitis, pneumonitis, or pericarditis. Sulfasalazine is also associated with sulfa-related hypersensitivity.

Antibiotics

Antibiotics have no primary role in the treatment of ulcerative colitis.

Corticosteroids

Systemic corticosteroids are effective therapies to induce remission for moderate-severe colitis and can be delivered orally or intravenously. However, the unacceptable adverse effect profile of steroids precludes their long-term use as maintenance therapies. Rectal steroids can be administered for patients with distal disease.

Thiopurine Immunosuppressants

Mercaptopurine (6-MP) and its prodrug azathioprine are purine analogues that interfere with nucleic acid synthesis and exhibit anti-inflammatory properties through their cytotoxic effect on inflammatory cells. They are effective therapies for maintenance of remission in ulcerative colitis and can facilitate withdrawal of steroids in patients who are otherwise steroid-dependent. Adverse effects include allergic reactions, infection, pancreatitis, bone marrow suppression, or hepatitis. Additionally, there is a slightly increased risk of lymphoma. Bone marrow suppression and therapeutic efficacy are related to genetic polymorphisms of the thiopurine-S-methyltransferase enzyme which can be measured to allow customized dosing to enhance both safety and efficacy.

Cyclosporine

Intravenous cyclosporine can be used as salvage therapy to induce remission in severe ulcerative colitis refractory to intravenous steroids. Although effective for short-term induction maintenance therapy with a thiopurine is required. Side effects include headache, tremor, paresthesias, seizures, hypertrichosis, hypertension, renal insufficiency, and opportunistic infections. The risk of pneumocystis pneumonia during cyclosporine therapy is substantial enough to warrant antimicrobial prophylaxis.

Tumor Necrosis Factor-a Inhibitors

Tumor necrosis factor (tumor necrosis factor) a is a pro-inflammatory cytokine that plays a key role in propagating the inflammatory cascade of Inflammatory bowel disease. Monoclonal antibodies targeted against tumor necrosis factor include infliximab and adalimumab and an Fab’ fragment linked to polyethylene glycol (certolizumab pegol) which are highly effective at inducing and maintaining clinical, endoscopic, and histologic improvement in Inflammatory bowel disease patients refractory to conventional therapies and are effective for healing Crohn disease fistulae. Infliximab is approved for induction and maintenance in ulcerative colitis, whereas adalimumab and certolizumab are currently only approved for Crohn disease.

The efficacy and safety profiles are comparable among the available anti-tumor necrosis factor agents. Opportunistic infections attributable to the immunosup-pressive mechanism of these medications include fungal pneumonias and tuberculosis. Consequently, patients should be properly immunized (pneumonia, tetanus, influenza, HPV) and routinely tested for latent tuberculosis prior to initiation of an anti-tumor necrosis factor therapy. Other side effects include allergic reactions, infusion or injection site reactions, delayed hypersensitivity reactions, drug-induced lupus, heart failure, and demyelinating disease.

Surgical Therapy for ulcerative colitis

Indications for surgery in ulcerative colitis include medically refractory disease, inability to wean off steroids, toxic megacolon, perforation, or confirmed dysplasia or cancer. Surgical options include proctocolectomy with permanent ileostomy, or total colectomy with ileal pouch anal anastomosis. These surgeries are considered curative for ulcerative colitis, although half of patients can develop inflammation in the ileal pouch necessitating antibiotics, steroids, or anti-tumor necrosis factor agents.

There are no pathognomonic markers for ulcerative colitis or Crohn disease.

Diagnosis is based upon endoscopy, histology, and imaging.

Therapeutic goals include induction and maintenance of clinical remissions.

Aminosalicylates are inductive and maintenance therapies for mild-moderate disease.

Corticosteroids are used to induce, but not maintain, remissions.

Anti-tumor necrosis factor agents can induce and maintain remissions when conventional agents fail.

Surgical removal of the colon is usually curative for ulcerative colitis.

Asacol

Azulfidine

Olsalazine

Balsalazide

Jennifer Bowles

Jennifer is a clinical pharmacologist. She helps doctors of all medical specialties choose medications. Jennifer consults about drug dosage, interactions, and side effects.