Chapter 47: Pharmacotherapy of Inflammatory Bowel Disease

Important insights into pathogenesis have emerged from genetic analyses of Crohn's disease. Mutations in the gene NOD2 (nucleotide-binding oligomerization domain-2; also called CARD15) are associated with both familial and sporadic Crohn's disease in whites (Hugot et al., 2001; Ogura et al., 2001). NOD2 is expressed in monocytes, granulocytes, dendritic cells, Paneth cells, and epithelial cells. It is proposed to function as an intracellular sensor for bacterial infection by recognizing peptidoglycans, thereby playing an important role in the natural immunity to bacterial pathogens. Consistent with this model, other studies have identified bacterial antigens, including pseudomonal protein I2 (Dalwadi et al., 2001) and a flagellin protein (Lodes et al., 2004), as dominant superantigens that induce the T_H1 response in Crohn's disease (shown as bacterial products in Figure 47–1). More recently, genome-wide studies have revealed other genes associated with IBD, whose identification may lead to the development of novel therapeutics (Cho, 2008)

Thus, these converging experimental approaches are generating novel insights into the pathogenesis of Crohn's disease that soon may translate into novel therapeutic approaches to IBD. The major therapeutic agents available for IBD are described next.

Oral sulfasalazine is effective in patients with mild or moderately active ulcerative colitis, with response rates in the range of 60-80% (Prantera et al., 1999). The usual dose is 4 g/day in four divided doses with food; to avoid adverse effects, the dose is increased gradually from an initial dose of 500 mg twice a day. Doses as high as 6 g/day can be used but cause an increased incidence of side effects. For patients with severe colitis, sulfasalazine is of less certain value, even though it is often added as an adjunct to systemic glucocorticoids. Regardless of disease severity, the drug plays a useful role in preventing relapses once remission has been achieved. In general, newer 5-ASA preparations have similar therapeutic efficacy in ulcerative colitis with fewer side effects. Because they lack the dose-related side effects of sulfapyridine, the newer formulations can be used to provide higher doses of mesalamine with some improvement in disease control. The usual doses to treat active disease are 800 mg three times a day for asacol and 1 g four times a day for pentasa. Lower doses are used for maintenance (e.g., asacol, 800 mg twice a day). Although some studies have suggested that a given preparation may be superior in treating colonic disease, there is no consensus on this issue.

The efficacy of 5-ASA preparations (e.g., sulfasalazine) in Crohn's disease is less striking, with modest benefit at best in controlled trials. Sulfasalazine has not been shown to be effective in maintaining remission and has been replaced by newer 5-ASA preparations. Some studies have reported that both asacol and pentasa are more effective than placebo in inducing remission in patients with Crohn's disease (particularly colitis), although higher doses than those typically used in ulcerative colitis are required. The role of mesalamine in maintenance therapy for Crohn's disease is controversial, and there is no clear benefit of continued 5-ASA therapy in patients who achieve medical remission (Camma et al., 1997). Because they largely bypass the small intestine, the second-generation 5-ASA prodrugs such as olsalazine and balsalazide do not have a significant effect in small-bowel Crohn's disease.

Topical preparations of mesalamine suspended in a wax matrix suppository (rowasa) or in a suspension enema (canasa) are effective in active proctitis and distal ulcerative colitis, respectively. They appear to be superior to topical hydrocortisone in this setting, with response rates of 75-90%. Mesalamine enemas (4 g/60 mL) should be used at bedtime and retained for at least 8 hours; the suppository (500 mg) should be used two to three times a day with the objective of retaining it for at least 3 hours. Response to local therapy with mesalamine may occur within 3-21 days; however, the usual course of therapy is from 3-6 weeks. Once remission has occurred, lower doses are used for maintenance.

Pharmacokinetics. Approximately 20-30% of orally administered sulfasalazine is absorbed in the small intestine. Much of this is taken up by the liver and excreted unmetabolized in the bile; the rest (~10%) is excreted unchanged in the urine. The remaining 70% reaches the colon, where, if cleaved completely by bacterial enzymes, it generates 400 mg mesalamine for every gram of the parent compound. Thereafter, the individual components of sulfasalazine follow different metabolic pathways. Sulfapyridine, which is highly lipid soluble, is absorbed rapidly from the colon. It undergoes extensive hepatic metabolism, including acetylation and hydroxylation, conjugation with glucuronic acid, and excretion in the urine. The acetylation phenotype of the patient determines plasma levels of sulfapyridine and the probability of side effects; rapid acetylators have lower systemic levels of the drug and fewer adverse effects. By contrast, only 25% of mesalamine is absorbed from the colon, and most of the drug is excreted in the stool. The small amount that is absorbed is acetylated in the intestinal mucosal wall and the liver and then excreted in the urine. Intraluminal concentrations of mesalamine therefore are very high (~1500 μg/mL or 10 mM in patients taking a typical dose of 3 g/day).

The pH-sensitive coatings (methyl-methacrylate methacrylic acid copolymer) of asacol (eudagrit) and lialda/mezavant limit gastric and small intestinal absorption of 5-ASA, as assessed by urinary, ileostomal, and fecal measurements of the various metabolites. The pharmacokinetics of pentasa differ somewhat. The ethylcellulose-coated micro-granules are released in the upper GI tract as discrete prolonged-release units of mesalamine. Acetylated mesalamine can be detected in the circulation within an hour after ingestion, indicating some rapid absorption, but some intact micro-granules also can be detected in the colon. Because it is released in the small bowel, a greater fraction of pentasa is absorbed systemically compared with the other 5-ASA preparations.

Adverse Effects. Side effects of sulfasalazine occur in 10-45% of patients with ulcerative colitis and are related primarily to the sulfa moiety. Some are dose related, including headache, nausea, and fatigue. These reactions can be minimized by giving the medication with meals or by decreasing the dose. Allergic reactions include rash, fever, Stevens-Johnson syndrome, hepatitis, pneumonitis, hemolytic anemia, and bone marrow suppression. Sulfasalazine reversibly decreases the number and motility of sperm but does not impair female fertility. Sulfasalazine inhibits intestinal folate absorption and is usually administered with folate.

The newer mesalamine formulations generally are well tolerated, and side effects are relatively infrequent and minor. Headache, dyspepsia, and skin rash are the most common. Diarrhea appears to be particularly common with olsalazine (occurring in 10-20% of patients); this may be related to its ability to stimulate chloride and fluid secretion in the small bowel. Nephrotoxicity, although rare, is a more serious concern. Mesalamine has been associated with interstitial nephritis; although its pathogenic role is controversial, renal function should be monitored in all patients receiving these drugs. Both sulfasalazine and its metabolites cross the placenta but have not been shown to harm the fetus. Although less well studied, the newer formulations appear to be safe in pregnancy. The risks to the fetus from the consequences of uncontrolled IBD in pregnant women are believed to outweigh the risks associated with the therapeutic use of these agents.

The approach to glucocorticoid therapy in IBD differs somewhat from that in diseases such as asthma or rheumatoid arthritis. Initial doses are 40-60 mg of prednisone or equivalent per day; higher doses generally are no more effective. The glucocorticoid dose in IBD is tapered over weeks to months. Even with these slow tapers, however, efforts should be made to minimize the duration of therapy. Glucocorticoids induce remission in most patients with either ulcerative colitis or Crohn's disease (Faubion et al., 2001). Oral prednisone is the preferred agent for moderate to severe disease, and the typical dose is 40-60 mg once a day. Most patients improve substantially within 5 days of initiating treatment; others require treatment for several weeks before remission occurs. For more severe cases, glucocorticoids are given intravenously. Generally, methylprednisolone or hydrocortisone is used for intravenous therapy, although some experts believe that corticotropin (ACTH) is more effective in patients who have not previously received any steroids.

Topically acting agents (i.e., given by enema) have fewer adverse effects than systemic steroids but are also less effective in reducing remission. Glucocorticoid enemas are useful mainly in patients whose disease is limited to the rectum and left colon. 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. Patients with distal disease usually respond within 3-7 days. Absorption, although less than with oral preparations, is still substantial (up to 50-75%). 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.

Budesonide (entocort er) is an enteric-release form of a synthetic steroid that is used for ileocecal Crohn's disease (Greenberg et al., 1994; McKeage and Goa, 2002). It is proposed to deliver adequate steroid therapy to a specific portion of inflamed gut while minimizing systemic side effects owing to extensive first-pass hepatic metabolism to inactive derivatives. Topical therapy (e.g., enemas and suppositories) also is effective in treating colitis limited to the left side of the colon. Although the topical potency of budesonide is 200 times higher than that of hydrocortisone, its oral systemic bioavailability is only 10%. In some studies, budesonide was associated with a lower incidence of systemic side effects than prednisone, although data also indicate that systemic steroids are more effective in patients with higher Crohn's Disease Activity Index scores. Budesonide (9 mg/day for up to 8 weeks followed by 6 mg/day for maintenance of remission for up to 3 months) is effective in the acute management of mild-to-moderate exacerbations of Crohn's disease, but its role in maintaining remission has not been fully delineated (Hofer, 2003).

A significant number of patients with IBD fails to respond adequately to glucocorticoids and are either steroid-resistant or steroid- dependent. The reasons for this failure are poorly understood but may involve complications such as fibrosis or strictures in Crohn's disease, which will not respond to anti-inflammatory measures alone; local complications such as abscesses, in which case the use of glucocorticoids may lead to uncontrolled sepsis; and intercurrent infections with organisms such as cytomegalovirus and Clostridium difficile. Steroid failures also may be related to specific pharmacogenomic factors such as upregulation of the multidrug resistance (mdr) gene (Farrell et al., 2000) or altered levels of corticosteroid-binding globulin.

These drugs generally are used interchangeably with appropriate dose adjustments, typically azathioprine (2-2.5 mg/ kg) or mercaptopurine (1.5 mg/kg). As discussed later, the pathways by which they are metabolized are clinically relevant, and specific assays can be used to assess clinical response and to avoid side effects. Because of concerns about side effects, these drugs were used initially only in Crohn's disease, which lacks a surgical curative option. They now are considered equally effective in Crohn's disease and ulcerative colitis. These drugs effectively maintain remission in both diseases; they also may prevent (or, more typically, delay) recurrence of Crohn's disease after surgical resection. Finally, they are used successfully to treat fistulas in Crohn's disease. The clinical response to azathioprine or mercaptopurine may take weeks to months, such that other drugs with a more rapid onset of action (e.g., mesalamine, glucocorticoids, or infliximab) are preferred in the acute setting.

The decision to initiate immunosuppressive therapy depends on an accurate assessment of the risk/benefit ratio. In general, physicians who treat IBD believe that the long-term risks of azathioprine–mercaptopurine are lower than those of steroids. Thus these purines are used in glucocorticoid-unresponsive or glucocorticoid-dependent disease and in patients who have had recurrent flares of disease requiring repeated courses of steroids. Additionally, patients who have not responded adequately to mesalamine but are not acutely ill may benefit by conversion from glucocorticoids to immunosuppressive drugs. Immunosuppressives therefore may be viewed as steroid-sparing agents.

Adverse effects of azathioprine–mercaptopurine can be divided into three general categories: idiosyncratic, dose related, and possible. Although the therapeutic effects of azathioprine– mercaptopurine often are delayed, their adverse effects occur at any time after initiation of treatment and can affect up to 10% of patients. The most serious idiosyncratic reaction is pancreatitis, which affects ~5% of patients treated with these drugs. Fever, rash, and arthralgias are seen occasionally, whereas nausea and vomiting are somewhat more frequent. The major dose-related adverse effect is bone marrow suppression, and circulating blood counts should be monitored closely when therapy is initiated and at less frequent intervals during maintenance therapy (e.g., every 3 months). Elevations in liver function tests also may be dose related. Although keeping drug levels in the appropriate range diminishes these adverse effects, they can occur even with therapeutic serum levels of 6-thioguanine nucleotides. The serious adverse effect of cholestatic hepatitis is relatively rare. Although the increased risk of infection is a significant concern with immunosuppressives, especially if pancytopenia occurs, infections are linked more closely to concomitant glucocorticoid therapy than to the immunosuppressives (Aberra et al., 2003).

Immunosuppressive regimens given in the setting of cancer chemotherapy or organ transplants have been associated with an increased incidence of malignancy, particularly non-Hodgkin's lymphoma. Definitive conclusions about the causative roles of azathioprine–mercaptopurine in lymphomas are complicated by the possible increased incidence of lymphomas in IBD per se and by the relative rarity of these cancers. The increased risk, if any, must be relatively small.

The plasma t_1/2 of mercaptopurine is limited by its relatively rapid (i.e., within 1-2 hours) uptake into erythrocytes and other tissues. Following this uptake, differences in TPMT activity determine the drug's fate. Approximately 80% of the U.S. population has what is considered "normal" metabolism, whereas 1 in 300 individuals has minimal TPMT activity. In the latter setting, mercaptopurine metabolism is shifted away from 6-methyl-mercaptopurine and driven toward 6-thioguanine nucleotides, which can severely suppress the bone marrow. About 10% of people have intermediate TPMT activity; given a similar dose, these individuals will tend to have higher 6-thioguanine levels than the normal metabolizers. Finally, ~10% of the population is considered rapid metabolizers. In these individuals, mercaptopurine is shunted away from 6-thioguanine nucleotides toward 6-MMP, which has been associated with abnormal liver function tests. In addition, relative to normal metabolizers, the 6-thioguanine levels of these rapid metabolizers are lower for an equivalent oral dose, possibly reducing therapeutic response. Given this variability, some experts evaluate an individual's TPMT activity status prior to initiating treatment with thiopurines and also measure 6-thioguanine/6-MMP levels in individuals not responding to therapy. To avoid these complexities, treatment with 6-thioguanine was explored; unfortunately, 6-thioguanine is associated with a high incidence of an uncommon liver abnormality, hepatic nodular regeneration, and associated portal hypertension; 6-thioguanine therapy of IBD therefore has been abandoned.

Xanthine oxidase in the small intestine and liver converts mercaptopurine to thiouric acid, which is inactive as an immunosuppressant. Inhibition of xanthine oxidase by allopurinol diverts mercaptopurine to more active metabolites such as 6-thioguanine and increases both immunosuppressant and potential toxic effects. Thus, patients on mercaptopurine should be warned about potentially serious interactions with medications used to treat gout or hyperuricemia, and the dose should be decreased to 25% of the standard dose in subjects who are already taking allopurinol.

As with azathioprine–mercaptopurine, methotrexate generally is reserved for patients whose IBD is either steroid-resistant or steroid-dependent. In Crohn's disease, it both induces and maintains remission, generally with a more rapid response than that seen with mercaptopurine or azathioprine (Feagan et al., 1995). Its use in ulcerative colitis has not been thoroughly investigated.

Therapy of IBD with methotrexate differs somewhat from its use in other autoimmune diseases. Most important, higher doses (e.g., 15-25 mg/week) are given parenterally. The increased efficacy with parenteral administration may reflect the unpredictable intestinal absorption at higher doses of methotrexate. For unknown reasons, the incidence of methotrexate-induced hepatic fibrosis in patients with IBD is lower than that seen in patients with psoriasis. Use of methotrexate for treatment of IBD has largely been supplanted by biological therapies (such as anti-TNFα antibodies).

Cyclosporine is effective in patients with severe ulcerative colitis who have failed to respond adequately to glucocorticoid therapy. Between 50% and 80% of these severely ill patients improve significantly (generally within 7 days) in response to intravenous cyclosporine (2-4 mg/kg per day), sometimes avoiding emergent colectomy. Careful monitoring of cyclosporine levels is necessary to maintain a therapeutic level in whole blood between 300 and 400 ng/mL.

Oral cyclosporine is less effective as maintenance therapy in Crohn's disease, perhaps because of its limited intestinal absorption. In this setting, long-term therapy with neoral or gengraf (formulations of cyclosporine with increased oral bioavailability) may be more effective, but this has not been studied fully. The calcineurin inhibitors can be used to treat fistulous complications of Crohn's disease. A significant rapid response to intravenous cyclosporine has been observed; however, frequent relapses accompany oral cyclosporine therapy, and other medical strategies are required to maintain fistula closure. Thus, the calcineurin inhibitors generally are used to treat specific problems over a short term while providing a bridge to longer-term therapy (Sandborn, 1995).

Other immunomodulators that are being evaluated in IBD include the calcineurin inhibitor tacrolimus (FK 506, prograf), mycophenolate mofetil and mycophenolate (cellcept, myfortic), inhibitors of inosine monophosphate dehydrogenase to which lymphocytes are especially susceptible (Chapter 35).

Although infliximab was designed specifically to target TNFα, it may have more complex actions. Infliximab binds membrane-bound TNFα and may cause lysis of these cells by antibody-dependent or cell-mediated cytotoxicity. Thus, infliximab may deplete specific populations of subepithelial inflammatory cells. These effects, together with its mean terminal plasma t_1/2 of 8-10 days, may explain the prolonged clinical effects of infliximab.

Infliximab (5 mg/kg infused intravenously at intervals of several weeks to months) decreases the frequency of acute flares in approximately two-thirds of patients with moderate to severe Crohn's disease and also facilitates the closing of enterocutaneous fistulas associated with Crohn's disease (Present et al., 1999). Its longer-term role in Crohn's disease is evolving, but emerging evidence supports its efficacy in maintaining remission (Rutgeerts et al., 2004) and in preventing recurrence of fistulas (Sands et al., 2004). The combination of infliximab and azathioprine is more effective than infliximab alone in induction of remission and mucosal healing in steroid-resistant patients (Rutgeerts et al., 2009). In contrast, there appears to be no synergistic benefit of the combination of methotrexate and infliximab. Infliximab has also proven to be an effective treatment for refractory ulcerative colitis (Rutgeerts et al., 2009).

The use of infliximab as a biological response modifier raises several important considerations. Both acute (fever, chills, urticaria, or even anaphylaxis) and subacute (serum sickness–like) reactions may develop after infliximab infusion, but a frank lupus-like syndrome occurs only rarely. Antibodies to infliximab can decrease its clinical efficacy. Each year, at least 10% of patients on infliximab have to stop therapy because of loss of response or intolerance (Rutgeerts et al., 2009). Strategies to minimize the development of these antibodies (e.g., treatment with glucocorticoids or other immunosuppressives) may be critical to preserving infliximab efficacy for either recurrent or chronic therapy (Farrell et al., 2003). Other proposed strategies to overcome the problem of "antibody resistance" include increasing the dose of infliximab or decreasing the interval between infusions.

Infliximab therapy is associated with increased incidence of respiratory infections; of particular concern is potential reactivation of tuberculosis or other granulomatous infections with subsequent dissemination. The FDA recommends that candidates for infliximab therapy be tested for latent tuberculosis with purified protein derivative, and patients who test positive should be treated prophylactically with isoniazid. However, anergy with a false-negative skin test has been noted in some patients with Crohn's disease, and some experts routinely perform chest radiographs to look for active or latent pulmonary disease. Infliximab also is contraindicated in patients with severe congestive heart failure (New York Heart Association classes III and IV) and should be used cautiously in class I or II patients. As with the immunosuppressives, there is concern about the possible increased incidence of non-Hodgkin's lymphoma, but a causal role has not been established. Finally, the significant cost of biological therapies such as infliximab is an important consideration.

Adalimumab (humira) is a humanized recombinant human IgG₁ monoclonal antibody against TNFα. It is effective in inducing remission in mild to moderate, severe, and fistulizing Crohn's disease (Rutgeerts et al., 2009). Unfortunately, adalimumab cannot be used to rescue patients who have lost responsiveness to another anti-TNFα antibody, such as infliximab. Certolizumab pegol (cimzia) is a pegylated humanized fragment antigen binding (Fab) that binds TNFα. It is approved in the U.S. for the treatment of Crohn's disease. It appears to have comparable efficacy to that of adalimumab and infliximab for the treatment of Crohn's disease, although direct comparative studies have not been performed (Rutgeerts et al., 2009). With both adalimumab and certolizumab pegol, immunogenicity appears to be less of a problem than that associated with infliximab.

Another anti-TNFα agent, Etanercept (enbrel), is a fusion protein of the ligand-binding portion of the TNFα receptor and the Fc portion of human IgG₁. This construct binds to TNFα and blocks its biologic effects but is ineffective in Crohn's disease.

Natalizumab (tysabri) is a humanized monoclonal antibody against α4-integrin (also known as VLA-4). Binding of the antibody to this adhesion molecule will reduce extravasation of certain leukocytes (e.g., lymphocytes), preventing them from migrating to sites of inflammation where they may exacerbate tissue injury. In 2008, natalizumab was approved in the U.S. for induction and maintenance of remission of moderate to severe Crohn's disease. Natalizumab had previously been withdrawn from the market and carries a black box warning because it appears to interact with other immune-modulating drugs to increase the risk of progressive multifocal leukoencephalopathy (PML). Thus, natalizumab is contraindicated for use with other immunomodulators. Because of the capacity of corticosteroids to produce immunosuppression, patients taking natalizumab for the treatment of Crohn's disease should have their doses reduced before starting natalizumab treatment.

The role of anti-TNF therapies for steroid-refractory or steroid-dependent ulcerative colitis is less clear. The rationale for their use is based on finding elevated levels of TNFα in the mucosa of patients. Large controlled clinical trials have demonstrated that anti-TNF agents significantly reduce the severity of the inflammation. The rates of clinical remission range from 26-34%, with endoscopic healing in about half the treated patients. Unlike Crohn's disease, ulcerative colitis is cured with surgery; thus the cost and serious adverse events associated with anti-TNF therapy need to be balanced with the effectiveness of the drug at preventing the need for colectomy. Currently, it is not known how effective anti-TNF therapies are for prevention, as opposed to delay, of colectomy.

Metronidazole (Sutherland et al., 1991), ciprofloxacin (Arnold et al., 2002), and clarithromycin are the antibiotics used most frequently. They are more beneficial in Crohn's disease involving the colon than in disease restricted to the ileum. Specific Crohn's disease-related complications that may benefit from antibiotic therapy include intra-abdominal abscess and inflammatory masses, perianal disease (including fistulas and perirectal abscesses), small-bowel bacterial overgrowth secondary to partial small-bowel obstruction, secondary infections with organisms such as C. difficile, and post-operative complications. Metronidazole may be particularly effective for the treatment of perianal disease. Post-operatively, metronidazole and related compounds have been shown to delay the recurrence of Crohn's disease. In one study, a 3-month course of metronidazole (20 mg/kg per day) prolonged the time to both endoscopic and clinical recurrence (Rutgeerts et al., 1995). The significant side effects of prolonged systemic antibiotic use must be balanced against their potential benefits, and definitive data to support their routine use are lacking.