Management of

inflammatory bowel
disease
Dr. Sumithra Appava

S Inflammatory bowel disease (IBD) is a spectrum of chronic,

idiopathic, inflammatory intestinal conditions.

S IBD causes significant gastrointestinal (GI) symptoms that include

diarrhea, abdominal pain, bleeding, anemia, and weight loss.

S IBD also is associated with a variety of extraintestinal

manifestations, including arthritis, ankylosing spondylitis,

sclerosing cholangitis, uveitis, iritis, pyoderma gangrenosum, and
erythema nodosum.
S IBD conventionally is divided into two major subtypes: ulcerative

colitis and Crohn's disease.

S Ulcerative colitis is characterized by confluent mucosal

inflammation of the colon starting at the anal verge and

extending proximally for a variable extent (e.g., proctitis, leftsided colitis, or pancolitis).
S Crohn's disease, by contrast, is characterized by transmural

inflammation of any part of the GI tract but most commonly the

area adjacent to the ileocecal valve. The inflammation in
Crohn's disease is not necessarily confluent, frequently leaving
"skip areas" of relatively normal mucosa. The transmural nature
of the inflammation may lead to fibrosis and strictures or,
alternatively, fistula formation.

S The peak age of onset of UC and CD is between 15 and 30 years.

S A second peak occurs between the ages of 60 and 80.

S The male to female ratio for UC is 1:1 and for CD is 1.8:1.
S UC and CD have two- to fourfold increased frequency in Jewish

populations in the United States, Europe, and South Africa.

S The prevalence decreases progressively in non-Jewish white,

African-American, Hispanic, and Asian populations

Goals of pharmacotherapy in
IBD
S Controlling acute exacerbations of the disease,

maintaining remission, and treating specific complications

such as fistulas.
S Specific drugs may be better suited for one or the other

of these aims.

Treatment
S 5-ASA Agents

S Nutritional Therapies

S Glucocorticoids

S Supportive Treatment

S Antibiotics

S VTE Prophylaxis

S Immunomodulators
S Methotrexate (MTX)

S Cyclosporine (CSA)
S Tacrolimus
S Biologic Therapies

5-ASA Agents

S Effective at inducing and maintaining remission in UC

S Limited role in inducing remission in CD, no clear role in

maintenance
S MOA: Promotion of peroxisome proliferator-activated receptor-

c; reduction of prostaglandin synthesis via inhibition of cyclooxygenase; inhibition of lipoxygenase; blockade of neutrophil
chemotaxis, interleukin-1 metabolism and mast cell release;
and inhibition of nuclear factor kappa B activation by tumour
necrosis factor alpha

Glucocorticoids

S Majority of patients with moderate-to-severe UC benefit from

oral or parenteral glucocorticoids

S Prednisolone is usually started at doses of 40-60 mg/d for

active UC that is unresponsive to 5-ASA therapy

S Parenteral glucocorticoids may be administered as

hydrocortisone, 300 mg/d, or methylprednisolone, 40-60 mg/d

S Topically applied glucocorticoids are also beneficial for distal

colitis and may serve as an adjunct in those who have rectal

involvement plus more proximal disease

S Topically acting agents (i.e., given by enema) have fewer

adverse effects than systemic steroids but are also less

effective in reducing remission.
S Glucocorticoid enemas are useful mainly in patients whose

disease is limited to the rectum and left colon.

S Hydrocortisone is available as a retention enema (100 mg/60

mL), and the usual dose is one 60-mL enema per night for 2 or
3 weeks. When administered optimally, the drug can reach up
to or beyond the descending colon.

S Patients with distal disease usually respond within 3-7

days. Absorption, although less than with oral

preparations, is still substantial (up to 50-75%).
S Hydrocortisone also can be given once or twice daily as a

10% foam suspension (CORTIFOAM) that delivers 80 mg

hydrocortisone per application; this formulation can be
useful in patients with very short areas of distal proctitis
and difficulty retaining fluid.

S Topically applied glucocorticoids are significantly

absorbed from the rectum and can lead to adrenal

suppression with prolonged administration.
S Topical 5-ASA therapy is more effective than topical

steroid therapy in the treatment of distal UC

S Glucocorticoids are also effective for treatment of

moderate-to-severe CD and induce a 60-70% remission

rate compared to a 30% placebo response.
S Controlled ileal-release budesonide has been nearly

equal to prednisolone for ileocolonic CD with fewer

glucocorticoid side effects.
S Budesonide is used for 2-3 months at a dose of 9 mg/d,

then tapered.

Glucocorticoids play no role in maintenance therapy in either UC or CD.

Once clinical remission has been induced, they should be tapered

according to the clinical activity, normally at a rate of no more than 5
mg/week.

The side effects are numerous, including fluid retention, abdominal striae,
fat redistribution, hyperglycemia, subcapsular cataracts, osteonecrosis,
osteoporosis, myopathy, emotional disturbances, and withdrawal
symptoms.

Most of these side effects, aside from osteonecrosis, are related to the
dose and duration of therapy

Antibiotics

S Antibiotics have no role in the treatment of active or quiescent UC.

However, pouchitis, which occurs in about a third of UC patients

after colectomy and ileal pouch-anal anastomosis (IPAA), usually
responds to treatment with metronidazole and/or ciprofloxacin.
S Metronidazole is effective in active inflammatory, fistulous, and

perianal CD and may prevent recurrence after ileal resection. The

most effective dose is 15-20 mg/kg per day in three divided doses;
it is usually continued for several months.
S Ciprofloxacin (500 mg bd) is also beneficial for inflammatory,

perianal, and fistulous CD

Immunomodulators: Azathioprine and 6Mercaptopurine

MOA: Impair purine biosynthesis and inhibit cell proliferation

Purine analogues commonly employed in the management of

glucocorticoid-dependent IBD

Efficacy can be seen as early as 3-4 weeks but can take up to 4-6 months

Azathioprine (2-3 mg/kg per day) or 6-MP (1-1.5 mg/kg per day) have
been employed successfully as glucocorticoid-sparing agents in up to twothirds of UC and CD patients previously unable to be weaned from
glucocorticoids

6-MP or azathioprine is effective for postoperative prophylaxis of CD

Methotrexate

S Methotrexate (MTX) inhibits dihydrofolate reductase,

resulting in impaired DNA synthesis. Additional antiinflammatory properties may be related to decreased IL-1
production.
S Intramuscular (IM) or subcutaneous (SC) MTX (25

mg/week) is effective in inducing remission and reducing

glucocorticoid dosage; 15 mg/week is effective in
maintaining remission in active CD.

Cyclosporine

S Calcineurin inhibitor

S Most effective when given at 24 mg/kg per day IV in

severe UC that is refractory to IV glucocorticoids

S Can be an alternative to colectomy

Tacrolimus

Macrolide antibiotic with immunomodulatory properties similar to CSA.

100 times as potent as CSA and is not dependent on bile or mucosal

integrity for absorption.

These pharmacologic properties enable tacrolimus to have good oral

absorption despite proximal small bowel Crohn's involvement.

It has shown efficacy in children with refractory IBD and in adults with
extensive involvement of the small bowel.

It is also effective in adults with steroid-dependent or refractory UC and

CD as well as refractory fistulizing CD.

Biologic therapies

S Often reserved for moderately to severely ill patients with

Crohn's disease, who have failed other therapies

S Among active CD patients refractory to glucocorticoids, 6-

MP, or 5-ASA, 65% will respond to IV infliximab (5

mg/kg); one-third will enter complete remission
S Reinfusion, typically every 8 weeks, is necessary to

continue therapeutic benefits in many patients.

S Adalimumab is a recombinant human monoclonal IgG1

antibody containing only human peptide sequences and

is injected subcutaneously.
S Certolizumab pegol is a PEGylated form of an anti-TNF

antibody administered SC once monthly.

S If a patient does not have an initial response to any anti-

TNF therapy, it was considered futile to try another.

(Before the approval of Natalizumab)

S Natalizumab is a recombinant humanized

immunoglobulin G4 antibody against 4 integrin that is

effective in the induction and maintenance of remission in
CD patients.
S It was approved February 2008 for the treatment of

patients with CD refractory or intolerant to anti-TNF

therapy.

S Treatment of acute disease in patients with UC is based

on disease activity
S Mild to moderate distal disease
S Oral aminosalicylates (ASAs), topical mesalamine or topical

steroids.
S Mild to moderate active proctitis
S Topical mesalamine, topical corticosteroid,
S Mesalamine enemas (refractory to topical steroids)
S Oral steroid/infliximab (refractory to other modalities of

treatment)

S Mild to moderate extensive colitis

S Oral sulfasalazine/5-ASA +/-topical therapy
S Oral steroids (refractory to combined oral and topical ASA

therapy or for those with severe symptoms requiring more

prompt improvement)
S Immunomodulators (those do not respond to oral steroids)
S Infliximab (steroid refractory, intolerant, or steroid-dependent
despite adequate doses of a thiopurine)

S Mild to moderate extensive colitis

S Oral sulfasalazine/5-ASA +/-topical therapy
S Oral steroids (refractory to combined oral and topical ASA

therapy or for those with severe symptoms requiring more

prompt improvement)
S Immunomodulators (refractory to steroids)
S Infliximab (steroid refractory, intolerant, or steroid-dependent
despite adequate doses of a thiopurine)

S Severe colitis
S Admission + IV steroids (methylprednisolone or

hydrocortisone)
S If hospitalization not necessary, oral prednisone, oral ASA
drugs, and topical medications
S Addition of infliximab if refractory to treatment
S tIf patient fails to improve within 3 to 5 days, colectomy or IV
cyclosporine should be considered.
S Fulminant disease
S Admission + IV glucocorticoid
S NBM and use of a decompression tube if small bowel ileus is

present
S IV cyclosporine/infliximab if refractory to treatment.

Crohn's Disease Activity Index

S Mild to moderate active ileocolic Crohn disease

S Budesonide/prednisolone if distal colonic disease is present
S Nutrition therapy is the first-line treatment for children
S Infliximab, adalimumab, or certolizumab pegol (refractory to

steroids)
S Methotrexate is also effective.
S Severe Crohn disease in any location
S Oral or intravenous steroids
S Antitumor necrosis factor therapy for refractory cases

Nutritional Therapies
S Dietary antigens may stimulate the mucosal immune response.

S Patients with active CD respond to bowel rest, along with TPN.

S Bowel rest and TPN are as effective as glucocorticoids at inducing

remission of active CD but are not effective as maintenance

therapy.
S Enteral nutrition in the form of elemental or peptide-based

preparations is also as effective as glucocorticoids or TPN, but

these diets are not palatable.
S Enteral diets may provide the small intestine with nutrients vital to

cell growth and do not have the complications of TPN.

S In contrast to CD, dietary intervention does not reduce

inflammation in UC.

Supportive treatment in IBD

S Analgesic, anticholinergic, and antidiarrheal agents play

supportive roles in reducing symptoms and improving quality of

life.
S These drugs should be individualized based on a patient's

symptoms and are supplementary to anti-inflammatory

medications.
S Oral iron, folate, and vitamin B12 should be administered as

indicated.
S Loperamide or diphenoxylate can be used to reduce the

frequency of bowel movements and relieve rectal urgency in

patients with mild disease; these agents are contraindicated in
patients with severe disease because they may predispose to
the development of toxic megacolon.

S Cholestyramine can be used to prevent bile saltinduced

colonic secretion in patients who have undergone limited

ileocolic resections.
S Anticholinergic agents (dicyclomine hydrochloride,etc.)

are used to reduce abdominal cramps, pain, and rectal

urgency. As with the anti-diarrheal agents, they are
contraindicated in severe disease or when obstruction is
suspected.

VTE Prophylaxis

S For patients with active colitis, the risk of venous

thromboembolism (VTE) is increased 15-fold. The most

common sites involved are the deep veins of the
extremities and/or pulmonary vasculature.
S Therefore, primary prophylaxis is indicated for any patient

admitted to the hospital for management of an IBD flare.

Surgical therapy

IBD and Pregnancy

S Sulfasalazine, mesalamine, and balsalazide are safe for use in

pregnancy and nursing, but additional folate supplementation must

be given with sulfasalazine. Topical 5-ASA agents are also safe
during pregnancy and nursing.
S Glucocorticoids are generally safe for use during pregnancy and

are indicated for patients with moderate to severe disease activity.

The amount of glucocorticoids received by the nursing infant is
minimal.
S The safest antibiotics to use for CD in pregnancy for short periods

of time (weeks, not months) are ampicillin and cephalosporin.

S Metronidazole can be used in the second or third trimester.

Ciprofloxacin causes cartilage lesions in immature animals and

should be avoided

S 6-MP and azathioprine pose minimal or no risk during

pregnancy, but experience is limited

S Because of the lack of data, CSA should probably be

avoided unless the patient would otherwise require

surgery

S Methotrexate is contraindicated in pregnancy and

nursing.
S No increased risk of stillbirths, miscarriages, or

spontaneous abortions has been seen with infliximab,

adalimumab or certolizumab, all class B drugs. The antiTNF drugs are relatively safe in nursing as well because
they do not pass into breast milk.
S Natalizumab is a class C drug, and there is limited data

on pregnancy.

References

S Harrisons Principles of Internal Medicine, 18e

S CURRENT Diagnosis & Treatment: Gastroenterology,

Hepatology, & Endoscopy, 2e

S Goodman & Gilman's The Pharmacological Basis of

Therapeutics, 12e

Thank You