2483 Inflammatory Bowel Disease CHAPTER 326

with a meal. Lialda is a once-a-day formulation of mesalamine

(Multi-Matrix System [MMX]) designed to release mesalamine

in the colon. The MMX technology incorporates mesalamine into

a lipophilic matrix within a hydrophilic matrix encapsulated in a

polymer resistant to degradation at a low pH (<7) to delay release

throughout the colon. The safety profile appears to be comparable

to other 5-ASA formulations.

Apriso is a formulation containing encapsulated mesalamine

granules that delivers mesalamine to the terminal ileum and colon

via a proprietary extended-release mechanism (Intellicor). The

outer coating of this agent (Eudragit L) dissolves at a pH >6. In addition, there is a polymer matrix core that aids in sustained release

throughout the colon. Because Lialda and Apriso are given once

daily, an anticipated benefit is improved compliance compared with

two to four daily doses required for other mesalamine preparations.

Pentasa is another mesalamine formulation that uses an ethylcellulose coating to allow water absorption into small beads containing

the mesalamine. Water dissolves the 5-ASA, which then diffuses out

of the bead into the lumen. Disintegration of the capsule occurs in

the stomach. The microspheres then disperse throughout the entire

GI tract from the small intestine through the distal colon in both

fasted and fed conditions.

Salofalk Granu-Stix, an unencapsulated version of mesalamine,

has been in use in Europe for induction and maintenance of remission for several years.

Appropriate doses of the 5-ASA compounds are shown in

Table 326-8. Some 50–75% of patients with mild to moderate UC

improve when treated with 5-ASA doses equivalent to 2 g/d of

mesalamine; the dose response continues up to at least 4.8 g/d.

More common side effects of the 5-ASA medications include

headaches, nausea, hair loss, and abdominal pain. Rare side effects

of the 5-ASA medications include renal impairment, hematuria,

pancreatitis, and paradoxical worsening of colitis. Renal function

tests and urinalysis should be checked yearly.

Topical Rowasa enemas are composed of mesalamine and are

effective in mild-to-moderate distal UC. Combination therapy with

mesalamine in both oral and enema form is more effective than

either treatment alone for both distal and extensive UC.

Canasa suppositories composed of mesalamine are effective in

treating proctitis.

GLUCOCORTICOIDS

The majority of patients with moderate to severe UC benefit from

oral or parenteral glucocorticoids. Prednisone is usually started at

doses of 40–60 mg/d for active UC that is unresponsive to 5-ASA

therapy. Parenteral glucocorticoids may be administered as hydrocortisone, 300 mg/d, or methylprednisolone, 40–60 mg/d. A newer

glucocorticoid for UC, budesonide (Uceris), is released entirely in

the colon and has minimal to no glucocorticoid side effects. The

dose is 9 mg/d for 8 weeks, and no taper is required. Topically

applied glucocorticoids (hydrocortisone enemas or budesonide

foam) are also beneficial for distal colitis and may serve as an

adjunct in those who have rectal involvement plus more proximal

disease. Hydrocortisone enemas are significantly absorbed from

the rectum and can lead to adrenal suppression with prolonged

administration. Topical 5-ASA therapy is more effective than topical steroid therapy in the treatment of distal UC.

Glucocorticoids are also effective for treatment of moderate to

severe CD and induce a 60–70% remission rate compared to a 30%

placebo response. The systemic effects of standard glucocorticoid

formulations have led to the development of formulations that

are less well absorbed and have increased first-pass metabolism.

Controlled-ileal-release budesonide has been nearly equal to prednisone for ileocolonic CD with fewer glucocorticoid side effects.

Budesonide is used for 2–3 months at a dose of 9 mg/d and 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 5–10 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

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

However, pouchitis, which occurs in ~30–50% of UC patients after

colectomy and IPAA, usually responds to treatment with a variety

of antibiotics including metronidazole and ciprofloxacin. Some

patients require long-term treatment with antibiotics for chronic

pouchitis.

AZATHIOPRINE AND MERCAPTOPURINE

Azathioprine and mercaptopurine (MP) are purine analogues used

concomitantly with biologic therapy or, much less often, as the sole

immunosuppressants. Azathioprine is rapidly absorbed and converted to MP, which is then metabolized to the active end product,

thioinosinic acid, an inhibitor of purine ribonucleotide synthesis

and cell proliferation. Efficacy can be seen as early as 3–4 weeks but

can take up to 4–6 months. Adherence can be monitored by measuring the levels of 6-thioguanine and 6-methylmercaptopurine,

end products of MP metabolism. The doses used range from 2 to

3 mg/kg per day for azathioprine and 1 to 1.5 mg/kg per day for MP.

Although azathioprine and MP are usually safe, pancreatitis

occurs in 3–4% of patients, typically presents within the first few

weeks of therapy, and is completely reversible when the drug is

TABLE 326-8 Oral 5-Aminosalicylic Acid (5-ASA) Preparations

PREPARATION FORMULATION DELIVERY DOSING PER DAY

Azo-Bond

Sulfasalazine (500 mg) (Azulfidine)

Balsalazide (750 mg) (Colazal)

Sulfapyridine-5-ASA

Aminobenzoyl-alanine–5-ASA

Colon

Colon

3–6 g (acute)

2–4 g (maintenance)

6.75–9 g

Delayed-Release

Mesalamine (400, 800 mg) (Delzicol, Asacol HD)

Mesalamine (1.2 g) (Lialda)

Eudragit S (pH 7)

MMX mesalamine (SPD476)

Distal ileum-colon

Ileum-colon

2.4–4.8 g (acute)

1.6–4.8 g (maintenance)

2.4–4.8 g

Controlled-Release

Mesalamine (250, 500, 1000 mg) (Pentasa) Ethylcellulose microgranules Stomach-colon 2–4 g (acute)

1.5–4 g (maintenance)

Delayed- and Extended-Release

Mesalamine (0.375 g) (Apriso) Intellicor extended-release mechanism Ileum-colon 1.5 g (maintenance)

Abbreviation: MMX, Multi-Matrix System.

2484 PART 10 Disorders of the Gastrointestinal System

stopped. Other side effects include nausea, fever, rash, and hepatitis.

Bone marrow suppression (particularly leukopenia) is dose-related

and often delayed, necessitating regular monitoring of the complete blood cell count (CBC). Additionally, 1 in 300 individuals

lacks thiopurine methyltransferase, the enzyme responsible for drug

metabolism to inactive end products (6-methylmercaptopurine); an

additional 11% of the population are heterozygotes with intermediate enzyme activity. Both are at increased risk of toxicity because

of increased accumulation of active 6-thioguanine metabolites.

Although 6-thioguanine and 6-methylmercaptopurine levels can

be followed to determine correct drug dosing and reduce toxicity,

weight-based dosing is an acceptable alternative. CBCs and liver

function tests should be monitored frequently regardless of dosing

strategy.

One meta-analysis demonstrated a fourfold risk of lymphoma

in IBD patients on azathioprine and MP. The highest risk for thiopurine-associated lymphoma is in patients >65 years old actively

using thiopurines (yearly incidence rate per 1000 patient-years

of 5.41), with a moderate risk in those between the ages of 50 and

65 (incidence rate of 2.58 compared to an incidence rate of 0.37 in

patients <50 years old). Patients using thiopurines also have a twoto threefold increased risk of nonmelanoma skin cancers.

METHOTREXATE

MTX inhibits dihydrofolate reductase, resulting in impaired DNA

synthesis. Additional anti-inflammatory properties may be related

to decreases in the production of IL-1. It is used most often concomitantly with biologic therapy to decrease antibody formation

and improve disease response. Intramuscular (IM) or subcutaneous (SC) doses range from 15 to 25 mg/week. Potential toxicities include leukopenia and hepatic fibrosis, necessitating periodic

evaluation of CBCs and liver enzymes. The role of liver biopsy in

patients on long-term MTX is uncertain but is probably limited to

those with increased liver enzymes. Hypersensitivity pneumonitis is

a rare but serious complication of therapy.

CYCLOSPORINE

CSA is a lipophilic peptide with inhibitory effects on both the cellular and humoral immune systems. CSA blocks the production of

IL-2 by T helper lymphocytes. CSA binds to cyclophilin, and this

complex inhibits calcineurin, a cytoplasmic phosphatase enzyme

involved in the activation of T cells. CSA also indirectly inhibits

B-cell function by blocking helper T cells. CSA has a more rapid

onset of action than MP and azathioprine.

CSA is most effective when given at 2–4 mg/kg per day IV in

severe UC that is refractory to IV glucocorticoids, with 82% of

patients responding. CSA can be an alternative to colectomy. The

long-term success of oral CSA is not as dramatic, but if patients

are started on MP or azathioprine at the time of hospital discharge,

remission can be maintained. Levels as measured by monoclonal

radioimmunoassay or by the high-performance liquid chromatography assay should be maintained between 150 and 350 ng/mL.

CSA may cause significant toxicity; renal function should be

monitored frequently. Hypertension, gingival hyperplasia, hypertrichosis, paresthesias, tremors, headaches, and electrolyte abnormalities are common side effects. Creatinine elevation calls for dose

reduction or discontinuation. Seizures may also complicate therapy,

especially if the patient is hypomagnesemic or if serum cholesterol

levels are <3.1 mmol/L (<120 mg/dL). Opportunistic infections,

most notably Pneumocystis jirovecii pneumonia, may occur with

combination immunosuppressive treatment; antibiotic prophylaxis

with trimethoprim-sulfamethoxazole should be given.

To compare IV CSA versus infliximab, a large trial was conducted in Europe by the GETAID (Group d’Etudes Thérapeutiques des Affections Inflammatoires Digestives) group. The results

indicated identical 7-day response rates for CSA 2 mg/kg (with

doses adjusted for levels of 150–250 ng/mL) and infliximab 5 mg/kg,

with both groups achieving response rates of 85%. Serious infections occurred in 5 of 55 CSA patients and 4 of 56 infliximab

patients. Response rates were similar in the two groups at day 98

among patients treated with oral CSA versus infliximab at the

usual induction dose and maintenance dose regimen (40 and 46%,

respectively). In light of data showing equal efficacy of CSA and

infliximab in severe UC, more physicians are relying on infliximab

rather than CSA in these patients.

TACROLIMUS

Tacrolimus is a macrolide antibiotic with immunomodulatory properties similar to CSA but 100 times as potent and not dependent on

bile or mucosal integrity for absorption. Thus, tacrolimus has good

oral absorption despite proximal small-bowel Crohn’s involvement.

Tacrolimus is effective in children with refractory IBD and in adults

with extensive involvement of the small bowel. It is also effective in

adults with glucocorticoid-dependent or refractory UC and CD as

well as refractory fistulizing CD.

BIOLOGIC THERAPIES

Biologic therapy is now commonly given as an initial therapy for

patients with moderate to severe CD and UC to prevent future

complications of IBD. High-risk patients with UC who are more

likely to require biologics include those with moderate to severe

disease, steroid-dependent or steroid-refractory disease, and refractory pouchitis. High-risk patients with CD who are more likely to

require biologics include those who are <30 years old, with extensive disease, perianal or severe rectal disease and/or deep ulcerations in the colon, and stricturing or penetrating disease behavior.

The current goal of IBD treatment is to treat early in the disease

course, treat aggressively with biologics, check drug and drug

metabolite levels, administer dual therapy with immunomodulators

and biologics in appropriate patients, and aim for deep remission

(endoscopic and histologic remission). Patients who respond to

biologic therapies enjoy an improvement in clinical symptoms; a

better quality of life; less disability, fatigue, and depression; and

fewer surgeries and hospitalizations.

Anti-TNF Therapies TNF is a proinflammatory cytokine that

regulates immune cells to coordinate a systemic immune response.

Dysregulation of TNF production has been associated with

immune-mediated disorders including IBD, and inhibition of

TNF signaling is used in the treatment of IBD. Four TNF inhibitors are currently approved for the treatment of IBD: infliximab,

adalimumab, certolizumab pegol, and golimumab. Infliximab, a

chimeric IgG1 antibody against TNF-α, was the first biologic therapy approved for moderately to severely active inflammatory and

fistulizing CD and UC.

The SONIC (Study of Biologic and Immunomodulator-Naive

Patients with Crohn’s Disease) trial compared infliximab plus azathioprine, infliximab alone, and azathioprine alone in immunomodulator- and biologic therapy–naive patients with moderate to

severe CD. At 1 year, the infliximab plus azathioprine group had a

glucocorticoid-free remission rate of 46% compared with 35% for

infliximab alone and 24% for azathioprine alone. Complete mucosal

healing was noted in more patients at week 26 with the combined

approach compared with either infliximab or azathioprine alone

(44 vs 30 vs 17%). The adverse events were equal between groups.

A similar study in patients with moderate to severe UC showed

that after 16 weeks of therapy, UC patients receiving azathioprine

plus infliximab exhibited a glucocorticoid-free remission rate of

40%, compared to rates of 24 and 22% in those on azathioprine

and infliximab alone, respectively. Together, these studies support

a more aggressive therapy for moderate to severe CD and UC.

Trough infliximab levels can be checked, and if low, the dose can be

increased or the interval decreased.

Hospitalized patients with acute severe glucocorticoidrefractory UC have a high inflammatory burden and may develop a

protein-losing enteropathy, leading to an accelerated consumption,

excessive fecal wasting, and low serum concentrations of infliximab. Given a clear exposure–response relationship for infliximab in

patients with IBD, intensive infliximab dosing regimens have been

used in these patients.

2485 Inflammatory Bowel Disease CHAPTER 326

Adalimumab (ADA) is a recombinant human monoclonal IgG1

antibody containing only human peptide sequences and is injected

subcutaneously. ADA binds TNF and neutralizes its function by

blocking the interaction between TNF and its cell-surface receptor.

Therefore, it seems to have a similar mechanism of action to infliximab but with less immunogenicity. ADA is approved for treatment

of moderate to severe CD and UC. CHARM (Crohn’s Trial of the

Fully Human Adalimumab for Remission Maintenance) is an ADA

maintenance study in patients who responded to ADA induction

therapy. About 50% of the patients in this trial were previously

treated with infliximab. Remission rates ranged from 42 to 48% in

infliximab-naïve patients at 1 year compared with remission rates

of 31–34% in patients who had previously received infliximab. UC

results are similar, with a sustained remission rate at 1 year of 22%

(12.4% placebo) among anti–TNF-naïve patients and a sustained

remission rate at 1 year of 10.2% (3% placebo) among patients who

had previously received anti-TNF agents. In clinical practice, the

remission rate in both CD and UC patients taking ADA increases

with a dose increase to 40 mg weekly instead of every other week.

Certolizumab pegol is a pegylated form of an anti-TNF Fab

portion of an antibody administered SC once monthly. SC certolizumab pegol was effective for induction of clinical response in

patients with active inflammatory CD.

Golimumab is another fully human IgG1 antibody against TNF-α

and is currently approved for the treatment of moderately to

severely active UC. Like ADA and certolizumab, golimumab is

injected SC.

Side Effects of Anti-TNF Therapies

Development of Antibodies and Drug Levels The development of antibodies to infliximab is associated with an increased

risk of infusion reactions and a decreased response to treatment.

Current practice does not include giving on-demand or episodic

infusions in contrast to scheduled periodic infusions because

patients are most likely to develop antibodies. Anti-infliximab

antibodies are generally present when the quality of response or the

response duration to infliximab infusion decreases. Commercial

assays can detect both infliximab and ADA antibodies and measure

trough levels to determine optimal dosing. If a patient has high

anti-infliximab antibodies and a low trough level of infliximab,

it is best to switch to another anti-TNF therapy. If a patient has

a therapeutic anti-TNF level and active inflammatory symptoms,

the drug should be switched to a different class of biologic. Most

acute infusion reactions and serum sickness can be managed with

glucocorticoids and antihistamines. Some reactions can be serious

and would necessitate a change in therapy, especially if a patient has

anti-infliximab antibodies. It is now common practice to add an

immunomodulator such as azathioprine, MP, or MTX to anti-TNF

therapy to help prevent antibody formation.

Non-Hodgkin’s Lymphoma (NHL) The baseline risk of NHL in

CD patients is 2 in 10,000, slightly higher than in the general population. Azathioprine and/or MP therapy increases the risk to ~4

in 10,000. It is difficult to assess whether anti-TNF medications are

associated with lymphoma because most patients are also receiving

thiopurines. After adjustment for co-treatments, no excess risk of

lymphoma was found in a Danish study of a cohort of IBD patients

exposed to anti-TNF medications.

Hepatosplenic T-Cell Lymphoma (HSTCL) HSTCL is a nearly

universally fatal lymphoma in patients with or without CD. In

patients with CD, a total of 37 unique cases have been reported.

Eighty-six percent of the patients were male, and the median age

was 26 years. Patients had CD for a mean of 10 years before the

diagnosis of HSTCL. Thirty-six patients had used either MP or

azathioprine, and 28 patients had used infliximab.

Skin Lesions New-onset psoriasiform skin lesions develop in

nearly 5% of IBD patients treated with anti-TNF therapy. Most

often, these can be treated topically, and occasionally, anti-TNF

therapy must be decreased, switched, or stopped. Patients with IBD

may have a slight, unexplained, intrinsic higher risk of developing

melanoma. The risk of melanoma is increased almost twofold with

anti-TNF and not thiopurine use. The risk of nonmelanoma skin

cancer is increased with thiopurines and biologics, especially with

≥1 year of follow-up. Patients on these medications should have a

skin check at least once a year.

Infections All of the anti-TNF drugs are associated with an

increased risk of infections, particularly reactivation of latent tuberculosis and opportunistic fungal infections including disseminated

histoplasmosis and coccidioidomycosis. Patients should have a

purified protein derivative (PPD) or a QuantiFERON-TB Gold test

before initiation of anti-TNF therapy. Patients >65 years old have

a higher rate of infections and death on infliximab or ADA than

those <65 years old.

Other Acute liver injury due to reactivation of hepatitis B virus

and to autoimmune effects and cholestasis has been reported.

Rarely, infliximab and the other anti-TNF drugs have been associated with optic neuritis, seizures, new onset or exacerbation of

clinical symptoms, and radiographic evidence of central nervous

system demyelinating disorders, including multiple sclerosis. They

may exacerbate symptoms in patients with New York Heart Association functional class III/IV heart failure.

ANTI-INTEGRINS

Integrins are expressed on the cell surface of leukocytes and serve

as mediators of leukocyte adhesion to vascular endothelium.

α4-Integrin along with its β1 or β7 subunit interact with endothelial ligands termed adhesion molecules. Interaction between α4β7

and mucosal addressin cellular adhesion molecule (MAdCAM-1)

is important in lymphocyte trafficking to gut mucosa.

Natalizumab is a recombinant humanized IgG4 antibody against

α4-integrin and is effective in induction and maintenance of

patients with CD. The rates of response and remission at 3 months

are ~60 and 40%, respectively, with a sustained remission rate of

~40% at 36 weeks. Natalizumab is no longer widely used for CD due

to the risk of progressive multifocal leukoencephalopathy (PML).

Vedolizumab (VDZ), another leukocyte trafficking inhibitor, is

a monoclonal antibody directed against α4β7-integrin specifically

and has the ability to convey gut-selective immunosuppression.

Unlike natalizumab, it inhibits adhesion of a discrete gut-homing

subset of T lymphocytes to MAdCAM-1, but not to vascular adhesion molecule-1. VDZ decreases GI inflammation without inhibiting systemic immune responses or affecting T-cell trafficking to the

central nervous system. It may be prescribed as a first-line biologic

or after failure of a TNF antagonist in patients with CD or UC.

The VARSITY trial, a phase 3B, randomized, double-blind, double-dummy, active-controlled superiority trial, evaluated outcomes

among patients with UC who received either VDZ or ADA. Results

showed that, at week 52, patients who were treated with VDZ were

significantly more likely to be in clinical remission (31.3% VDZ vs

22.5% ADA) and show endoscopic improvement (39.7% VDZ vs

27.7% ADA). Glucocorticoid-free clinical remission was observed

in 12.6% of the VDZ group and 21.8% of patients who received

ADA, but the difference was not statistically significant. This trial

suggests that among patients with UC, VDZ should be considered

as first-line therapy and before treatment with ADA.

Ustekinumab, a fully human IgG1 monoclonal antibody, blocks

the biologic activity of IL-12 and IL-23 through their common p40

subunit by inhibiting the interaction of these cytokines with their

receptors on T cells, natural killer cells, and antigen-presenting

cells. In the UNITI trial, the remission rate for the highest 6 mg/kg

IV induction dose followed by a dose of 90 mg every 8 weeks was

41.7%, compared with 27.4% for placebo, at 22 weeks in patients

with CD no longer responding to anti-TNF therapy.

Similarly, the UNIFI trial evaluated ustekinumab as 8-week

induction and 44-week maintenance therapy in moderate to severe

UC. Induction rates at 8 weeks were 15.6% in the ustekinumab

group compared to 5.3% in the placebo group, and 44-week maintenance rates were 43.8% in the ustekinumab group compared to

2486 PART 10 Disorders of the Gastrointestinal System

24% in the placebo group. The rates of serious adverse events were

similar for ustekinumab and placebo in the UNITI and UNIFI trials. Therefore, ustekinumab is another option for the treatment of

moderate to severe CD and UC and is particularly appealing for use

in patients with concomitant psoriatic arthritis.

SMALL MOLECULES

Small molecules (drugs with molecular weight <1 kDa) are a new

class of orally administered medications developed for IBD that lack

the immunogenicity associated with monoclonal antibodies. The

advantage of small molecules is their ability to diffuse through cell

membranes into the intracellular space and alter cytokine signaling

pathways. This mechanism of action may be more efficacious compared to monoclonal antibodies that inhibit specific targets because

several cytokine pathways are involved in IBD pathogenesis and

inhibiting numerous cytokines may be synergistic. A key regulatory

pathway is the JAK/STAT pathway that activates transcription and

translation of proteins that mediate the immune response. Janus

kinase (JAK) is a family of intracellular, nonreceptor tyrosine kinases

that regulate cytokine signaling via the JAK/STAT pathway, ultimately

suppressing the immune response and inflammation. The JAK family

members include JAK1, JAK2, JAK3, and tyrosine kinase 2 (TYK2).

Tofacitinib is a reversible and competitive JAK inhibitor used for

the treatment of moderate to severe UC refractory to conventional

therapy. It competes with ATP to bind to the ATP-docking site of the

kinase domain of JAK. By competing with ATP, tofacitinib inhibits

phosphorylation and activation of JAK, leading to downstream

reduction of cytokine production and alteration of the immune

response. Although tofacitinib is a pan-JAK inhibitor, it has higher

specificity for JAK1 and JAK3 than for JAK2 and TYK2. The panJAK inhibition is concerning for adverse events and overall safety.

The efficacy of tofacitinib as induction and maintenance therapy,

as well as its safety profile, was evaluated in three phase 3, randomized, double-blind, placebo-controlled trials in adults with moderate

to severe UC refractory to conventional therapy including anti-TNFs. Patients who responded to induction therapy were eligible for

OCTAVE Sustain, a maintenance trial of tofacitinib 5 mg versus

10 mg versus placebo that continued through 52 weeks, with the

primary end point of clinical remission at 52 weeks. Remission rates

at 8 weeks in the OCTAVE Induction 1 and 2 trials were 18.5 and

16.6% in the tofacitinib groups, compared to 8.2 and 3.6% in the placebo groups, respectively. In the OCTAVE Sustain trial, remission

rates at 52 weeks were 34.3% with 5 mg and 40.6% with 10 mg of

tofacitinib, compared to 11.1% with placebo. A recent U.S. Food and

Drug Administration review concluded that there is an increased

risk of serious adverse events including heart attack, stroke, cancer,

blood clots, and death in patients with ulcerative colitis and rheumatoid arthritis who are prescribed tofacitinib. Patients who are at risk

for cardiovascular disease, are current or past smokers and/or are

over the age of 50 should consider alternative therapies.

OZANIMOD

Ozanimod is a potent sphingosine-1-phosphate (S1P1) receptor

modulator that binds selectively with high affinity to the S1P receptor subtypes S1P1 and S1P5, both of which are involved in immune

regulation. By preventing trafficking of disease-exacerbating lymphocytes to the gut, ozanimod may provide immunomodulatory

effects and moderate disease processes.

Ozanimod has very recently been approved for the treatment of

moderate to severe ulcerative colitis. It is administered as a daily capsule.

The biologic and small-molecule therapies used in daily practice

are detailed in Table 326-9.

NUTRITIONAL THERAPIES

Diet has long been thought to contribute to the pathogenesis of IBD

and may also be an avenue for managing disease activity. Diet plays

a significant role in shaping the gut microbiome, and dietary components may interact with the microbiome and stimulate a mucosal

immune response. In fact, active CD responds to exclusive enteral

nutrition (EEN) or bowel rest with TPN, interventions as effective

as glucocorticoids in inducing remission but not as effective for

maintenance therapy. In contrast to CD, active UC is not effectively

treated by elemental diets or TPN.

Dietary approaches to maintenance therapy in CD have largely

been adapted from epidemiologic studies; however, significant heterogeneity is noted among research study outcomes. In general, low

fiber, refined carbohydrates (especially sweetened beverages), animal

fats, red meat, and processed meat have been associated with onset

of IBD. Therefore, the overall dietary approach is to maximize fiber

intake, particularly from fruits and vegetables, and to limit consumption of higher-risk foods. Several defined diets adhere to these principles with some variation, including the Mediterranean diet pattern,

specific carbohydrate diet, semi-vegetarian diet, and IBD anti-inflammatory diet (IBD-AID). However, it remains unclear whether diet

studies will eventually lead to evidence-based nutrition guidelines.

Standard medical management of UC and CD is shown in

Fig. 326-12.

SURGICAL THERAPY

Ulcerative Colitis Nearly one-half of patients with extensive

chronic UC undergo surgery within the first 10 years of their illness.

The indications for surgery are listed in Table 326-10. Morbidity is

~20% for elective, 30% for urgent, and 40% for emergency proctocolectomy. The risks are primarily hemorrhage, contamination and

sepsis, and neural injury. The operation of choice is an IPAA.

Because UC is a mucosal disease, the rectal mucosa can be

dissected and removed down to the dentate line of the anus or

~2 cm proximal to this landmark. The ileum is fashioned into a

pouch that serves as a neorectum. This ileal pouch is then sutured

circumferentially to the anus in an end-to-end fashion. If performed carefully, this operation preserves the anal sphincter and

maintains continence. The overall operative morbidity is 10%, with

the major complication being bowel obstruction. Pouch failure

necessitating conversion to permanent ileostomy occurs in 5–10%

of patients. Some inflamed rectal mucosa is usually left behind, and

thus, endoscopic surveillance is necessary. Primary dysplasia of the

ileal mucosa of the pouch has occurred rarely.

Patients with IPAA usually have ~6–10 bowel movements a day.

On validated quality-of-life indices, they report better performance

in sports and sexual activities than ileostomy patients. The most

frequent complication of IPAA is pouchitis in ~30–50% of patients

with UC. This syndrome consists of increased stool frequency,

watery stools, cramping, urgency, nocturnal leakage of stool, arthralgias, malaise, and fever. Pouch biopsies may distinguish true pouchitis from underlying CD. Although pouchitis usually responds to

antibiotics, 3–5% of patients remain refractory and may require glucocorticoids, immunomodulators, biologics, or even pouch removal.

Crohn’s Disease The majority of patients with CD will require

at least one operation in their lifetime. The need for surgery is

related to duration of disease and the site of involvement. Patients

with small-bowel disease have an 80% chance of requiring surgery.

Those with colitis alone have a 50% chance. Surgery is an option

only when medical treatment has failed or complications dictate its

necessity. The indications for surgery are shown in Table 326-10.

Small-Intestinal Disease Because CD is chronic and recurrent, with no clear surgical cure, as little intestine as possible is

resected. Current surgical alternatives for treatment of obstructing

CD include resection of the diseased segment and strictureplasty.

Surgical resection of the diseased segment is the most frequently

performed operation, and in most cases, primary anastomosis can

be done to restore continuity. An end-to-end anastomosis may

provide the best opportunity for an optimal functional outcome,

compared to an antiperistaltic side-to-side anastomosis, which

creates a functional block to motility leading to distention and pain

at the anastomotic site in a subgroup of patients. If much of the

small bowel has already been resected and the strictures are short,

with intervening areas of normal mucosa, strictureplasties should

be done to avoid a functionally insufficient length of bowel. The

2487 Inflammatory Bowel Disease CHAPTER 326

TABLE 326-9 Biologic Agents in the Treatment of Inflammatory Bowel Disease

MEDICATION DOSAGE INDICATION SERIOUS TOXICITIES

OTHER COMMON SIDE

EFFECTS TESTING

Infliximab 5 mg/kg at 0, 2, and 6

weeks, then every 8

weeks; may increase

dose to 10 mg/kg every

4 weeks depending on

trough levels

Intensive dosing

for hospitalized

corticosteroid-refractory

patients

Moderate to severe

Crohn’s disease and

ulcerative colitis

Fistulizing Crohn’s disease

Increased risk of

infections (bacterial and

fungal), tuberculosis

(TB) reactivation,

hepatitis B reactivation,

lymphoma (controversial),

psoriasis, melanoma

and nonmelanoma skin

cancers, drug-induced

lupus

Contraindicated in

multiple sclerosis, class

III/IV congestive heart

failure

Infusion reactions Prior to infusion:

TB testing

Hepatitis B testing (HBsAb, HBsAb,

HBcAb)

Maintenance:

Skin check yearly

Influenza, Pneumovax 23, and

Prevnar 13 vaccinations

Hepatitis B vaccine if not immune

Adalimumab 160 mg day 0, 80 mg day

14 and then 40 mg every

14 days; may increase

to 40 mg every 7 days

depending on trough

levels

Moderate to severe

Crohn’s disease and

ulcerative colitis.

Fistulizing Crohn’s disease

As above Injection site reactions

(better with citrate-free

preparation)

As above

Certolizumab 400 mg on days 0 and 14,

then 400 mg every 28 days

Moderate to severe

Crohn’s disease

As above As above As above

Golimumab 200 mg on day 0, 100 mg

on day 14, then 100 mg

every 28 days

Moderate to severe

ulcerative colitis

As above As above As above

Vedolizumab 300 mg at 0, 2, and 6

weeks, then every 8

weeks; may increase

dose to 300 mg every 4

weeks

Moderate to severe

ulcerative colitis

(more effective than

adalimumab as first-line

therapy in one study)

No increased risk of

serious systemic or

opportunistic infections

No increased risk of

malignancy

Nasopharyngitis,

headache, arthralgias,

nausea

Prior to infusion:

TB testing

hepatitis B testing (HBsAb, HBsAg,

HBcAb)

Maintenance:

Influenza, Pneumovax 23, and

Prevnar 13 vaccinations

Hepatitis B vaccine if not immune

Natalizumab 300 mg IV every 4 weeks Moderate to severe

Crohn’s disease (not to be

used in combination with

other immunosuppressive

medications)

Progressive multifocal

leukoencephalopathy

(monitor anti-JCV

antibodies every 6 months

and stop if positive)

Headache, fatigue,

infusions reactions,

urinary tract infections,

arthralgia, pain in

extremity, rash,

gastroenteritis, vaginitis

Prior to infusion:

Anti-JCV antibody, TB testing

Hepatitis B testing (HBsAb, HBsAg,

HBcAb)

Maintenance:

Influenza, Pneumovax 23, and

Prevnar 13 vaccinations

Hepatitis B vaccine if not immune

Ustekinumab 6 mg/kg IV, then 90 mg

every 8 weeks; may

increase dose to 90 mg

every 4 weeks

Moderate to severe

Crohn’s disease and

ulcerative colitis

Reversible posterior

leukoencephalopathy

syndrome (presents

with headaches,

seizures, confusion, and

visual disturbances),

anaphylaxis, and

angioedema

Nasopharyngitis, upper

respiratory tract infection,

fatigue, headache

Prior to infusion:

TB testing

Hepatitis B testing (HBsAb, HBsAg,

HBcAb)

Maintenance:

Influenza, Pneumovax 23, and

Prevnar 13 vaccinations

Hepatitis B vaccine if not immune

Tofacitinib 10 mg bid; can decrease

to 5 mg bid when patient

in remission

Moderate to severe

ulcerative colitis

Increased risk of heart

attack, stroke, cancer,

blood clots, and death in

patients with ulcerative

colitis and rheumatoid

arthritis Patients who are

at risk for cardiovascular

disease, are current or

past smokers and/or are

over the age of 50 should

consider alternative

therapies.

Increased risk of viral

infections, including

herpes zoster, and

bacterial and invasive

fungal infections

Elevated lipids,

neutropenia, anemia,

elevated liver enzymes

Prior to infusion:

First dose of Shingrix recommended,

TB testing

Hepatitis B testing (HBsAb, HBsAg,

HBcAb)

Maintenance:

Influenza, Pneumovax 23, and

Prevnar 13 vaccinations

Hepatitis B vaccine if not immune

2488 PART 10 Disorders of the Gastrointestinal System

strictured area of intestine is incised longitudinally and the incision

sutured transversely, thus widening the narrowed area. Complications of strictureplasty include prolonged ileus, hemorrhage, fistula,

abscess, leak, and restricture.

Risk factors for early recurrence of disease include cigarette

smoking, penetrating disease (internal fistulas, abscesses, or other

evidence of penetration through the wall of the bowel), early recurrence since a previous surgery, multiple surgeries, and a young age

at the time of the first surgery. Aggressive postoperative treatment

with biologics should be considered for this group of patients. It is

also recommended to evaluate for endoscopic recurrence of CD via

a colonoscopy, if possible, 3–6 months after surgery.

Colorectal Disease A greater percentage of patients with

Crohn’s colitis require surgery for intractability, fulminant disease,

and anorectal disease. Several alternatives are available, ranging

from the use of a temporary loop ileostomy to resection of segments

of diseased colon or even the entire colon and rectum. For patients

with segmental involvement, segmental colon resection with primary anastomosis can be performed. In 20–25% of patients with

extensive colitis, the rectum is spared sufficiently to consider rectal

preservation. Most surgeons believe that an IPAA is contraindicated

in CD due to the high incidence of pouch failure. A diverting colostomy may help heal severe perianal disease or rectovaginal fistulas,

but disease almost always recurs with reanastomosis. These patients

often require a total proctocolectomy and ileostomy.

■ IBD AND PREGNANCY

Patients with quiescent UC and CD have normal fertility rates; the

fallopian tubes can be scarred by the inflammatory process of CD,

especially on the right side because of the proximity of the terminal

ileum. In addition, perirectal, perineal, and rectovaginal abscesses and

fistulas as well as pelvic surgery can result in dyspareunia. Infertility

in men can be caused by sulfasalazine but reverses when treatment is

stopped. Women with an IPAA have decreased fertility due to scarring

or occlusion of the fallopian tubes secondary to pelvic inflammation

and adhesions, although studies have shown that fertility is improved

with laparoscopic versus open IPAA.

Mild or quiescent UC or CD has no effect on birth outcomes. The

courses of CD and UC during pregnancy mostly correlate with disease

activity at the time of conception. Patients should be in remission for

6 months before conceiving. Most CD patients can deliver vaginally, but

cesarean delivery may be the preferred route of delivery for patients with

anorectal and perirectal abscesses and fistulas to reduce the likelihood

of fistulas developing or extending into the episiotomy scar. Unless they

desire multiple children, UC patients with an IPAA may consider a

cesarean delivery due to an increased risk of future fecal incontinence.

Sulfasalazine and all mesalamines are safe for use in pregnancy

and nursing with the caveat that additional folate supplementation

must be given with sulfasalazine. Topical 5-ASA agents are safe during

pregnancy and nursing. Glucocorticoids are generally safe for use during pregnancy and are indicated for patients with moderate to severe

Mild to Moderate Ulcerative Colitis Moderate to Severe Ulcerative Colitis

Mild to Moderate Crohn’s Disease

Moderate to Severe Crohn’s Disease Fistulizing Crohn’s Disease

Prednisone oral (induction

of remission only)

Hydrocortisone rectal

Budesonide rectal and/or oral

5-ASA oral and/or rectal

Cyclosporine IV

Tofacitinib

Biologic +/– MP/AZA/MTX

Hydrocortisone or Solumedrol IV

(induction of remission only)

Prednisone oral (induction of remission only)

Total

parenteral

nutrition

and bowel rest

Biologic +/–

MP/AZA/MTX

Prednisone oral (induction of

remission only)

Sulfasalazine (colon)

Budesonide (ileal and right colon)

Biologic +/– MP/AZA/MTX

Hydrocortisone or Solumedrol IV

(induction of remission only)

Prednisone oral (induction of remission only)

Total

parenteral

nutrition and

bowel rest

Abscess drainage and antibiotics

Biologic +/– MP/AZA/MTX

Tofacitinib

Biologic +/–

MP/AZA/MTX

FIGURE 326-12 Medical management of inflammatory bowel disease. 5-ASA, 5-aminosalicylic acid; CD, Crohn’s disease; UC, ulcerative colitis.

TABLE 326-10 Indications for Surgery

ULCERATIVE COLITIS CROHN’S DISEASE

Intractable disease Small Intestine

Fulminant disease Stricture and obstruction

Toxic megacolon unresponsive to medical therapy

Colonic perforation Massive hemorrhage

Massive colonic hemorrhage Refractory fistula

Extracolonic disease Abscess

Colonic obstruction Colon and rectum

Colon cancer prophylaxis Intractable disease

Colon dysplasia or cancer Fulminant disease

 Perianal disease unresponsive to medical

therapy

Refractory fistula

Colonic obstruction

Cancer prophylaxis

Colon dysplasia or cancer