40 Medical Management of Inflammatory Bowel Disease

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40

Medical Management of Inflammatory Bowel Disease

Stephen B. Hanauer, Wee-Chian Lim, and Miles Sparrow

555 Crohn’s disease and ulcerative colitis (UC) are chronic

inflammatory diseases of the gastrointestinal tract, collec- tively known as inflammatory bowel disease (IBD). IBD afflicts approximately 1.3 million Americans and seems to be increasing in frequency in many parts of the world,¹pro- ducing chronic relapsing symptoms that are associated with increased morbidity and decreased quality of life. Although its etiopathogenesis is yet to be fully elucidated, it is thought to involve a complex interplay of genetic, environmental, microbial, and immune factors. Since the discovery of sulfasalazine’s unanticipated efficacy in UC,²numerous agents have been added to the therapeutic “arsenal.” Recent advances in our knowledge of the immunopathogenesis of IBD have also opened an exciting new door to biologic therapy. Pharmacotherapy remains the cornerstone of IBD management, with most patients requiring lifelong therapy because of the chronicity of the disease and its typical onset before 30 years of age.³ Surgery is usually reserved for treating medically refractory disease or specific complications. With the exception of curative proctocolectomy in UC, neither medical nor surgical therapy can offer a cure for IBD. Therefore, the aims of therapy are to control symptoms, improve quality of life, and minimize short- and long-term complications of both the disease and its therapy.

An important principle in the medical therapy of IBD is that there are two phases to treatment: inducing symptomatic remission of active disease and maintaining this remission for the long term. Establishing the anatomic extent and clinical severity of disease is essential to guiding the therapeutic approach. Other important considerations include patient response to previous or current treatment, presence of complications, and side effects of the pharmacologic agents.

Tailoring treatment according to the patient’s unique needs and preferences has an important role in enhancing treatment adherence, which is crucial to an optimal long-term outcome.

Therapeutic strategies continue to evolve with advancing knowledge, and this chapter details the current approach to medical treatment in IBD.

Medical Management of Crohn’s Disease

Crohn’s disease, a form of chronic idiopathic IBD, is manifested by focal, asymmetric, transmural, and, occasionally, granulomatous inflammation affecting any part of the gastrointestinal tract, from mouth to anus. The incidence in the United States and other Westernized countries is estimated at 5/100,000 with a prevalence of 50/100,000. Although any age group can be affected, diagnosis is usually made in the second and third decades of life.

This section will cover both the induction and maintenance phases of medical treatments for Crohn’s disease, with therapeutic strategies organized according to disease severity. Special mention will be made of the role of infliximab, because this has now become standard therapy for management of moderate–severe and fistulizing Crohn’s disease. Areas of particular interest to our surgical col- leagues will then be discussed including medical management of perianal fistulae, indications for surgery, and medical strategies to reduce postoperative recurrence of Crohn’s disease.

Induction Therapy for Crohn’s Disease Mild–Moderate Crohn’s Disease

Patients with mild–moderate Crohn’s disease are generally ambulatory and tolerate liquid and solid intake. These patients typically do not have severe abdominal tenderness, inflammatory masses, bowel obstruction, weight loss of > 10%, and are not manifesting signs of systemic toxicity [e.g., fever (> 37.5°C), tachycardia (> 90/minute), anemia (< 75%) of normal value, an increased erythrocyte sedimentation rate (ESR) (> 30 mm/hour)].⁴ Aminosalicylates and antibiotics are the mainstay of therapy for mild–moderate Crohn’s disease, although the topically acting steroid, budesonide, is increas- ingly being used as a drug of choice for mild–moderate disease, with minimal side effects.

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Sulfasalazine (Azulfidine®) was the first aminosalicylate trialed in the 1970s and 1980s. It was proven to be beneficial over placebo in the treatment of ileocolonic and colonic Crohn’s disease when given in doses of 3–6 g daily, with 40%–50% of patients achieving clinical remission.⁵ Sulfasalazine, is a compound consisting of sulfapyridine and 5-aminosalicylic acid (5-ASA, also known as mesalamine) attached by an azo bond that is cleaved into the active moiety, 5-ASA and its carrier molecule, sulfapyridine, by colonic bacterial azo-reductases and hence has minimal efficacy in Crohn’s disease of the small bowel.²Its use is also limited by more side effects at higher doses secondary to the systemic absorption of sulfapyridine. Slow acetylators are more apt to develop intolerance, including headache, nausea, vomiting, and dyspepsia, whereas dose-independent hypersensitivity reactions include fever, rash, pneumonitis, hepatitis, pancreatitis, hemolytic anemia, bone marrow suppression, and reversible sperm abnormalities. Sulfasalazine also impairs folate absorption and patients receiving sulfasalazine should receive daily folic acid (1 mg/day) supplements.

Because of these limitations with sulfasalazine, newer formulations of 5-ASA or mesalamine were developed that minimized side effects and utilized varying drug delivery systems to deliver the active drug intact to the mucosa of the small bowel and colon. Delayed-release formulations of mesalamine include Eudragit-S coated mesalamine (Asacol®) that releases 5-ASA in the terminal ileum and cecum at pH 7, and Eudragit- L–coated mesalamine formulations (Salofalk®, Mesasal®, and Claversal®) that releases in the mid-ileum at pH 6.

Pentasa® (a sustained-release formulation of mesalamine microgranules enclosed within a semipermeable membrane of ethylcellulose) is designed for controlled release throughout the small and large intestine, beginning in the duodenum.

Newer azo-bonded formulations designed for release in the colon include the 5-ASA dimer, olsalazine (Dipentum®), and balsalazide (Colazal®), which is composed of 5-ASA mole- cules azo-bonded to 4-aminobenzoyl-β alanine. Mesalamine in doses of 3.2–4.0 g daily is well tolerated and has been successful in inducing remission in 40%–50% of patients with mild–moderate Crohn’s disease. However, results of clinical trials have produced conflicting results, and there have been no adequately powered trials to date comparing mesalamine with sulfasalazine in Crohn’s disease.⁶ The use of rectal mesalamine, although frequently used for left-sided Crohn’s disease, is not supported by evidence from clinical trials.

Antibiotics are an alternative first-line therapy in mild–moderate Crohn’s disease, and seem to work better in patients with colonic rather than small bowel disease.

Metronidazole, when compared with sulfasalazine in a crossover trial, had initial similar efficacy, although more patients who failed sulfasalazine therapy responded when

“crossed over” to metronidazole than vice versa.⁷Side effects to metronidazole include a metallic taste, and most impor- tantly peripheral neuropathy that can be irreversible, when administered long term in doses of >1 g/day.⁸

A more effective and possibly better-tolerated alternative to metronidazole is ciprofloxacin in doses of 1 g daily. Trials using this dose show it to be equally efficacious to mesalamine, 4 g/day, with approximately 50% of the patients entering clinical remission.⁹In uncontrolled trials, combina- tions of ciprofloxacin and metronidazole have yielded superior results to using either agent alone.^10,11

Controlled-release oral budesonide is the only Food and Drug Administration (FDA)-approved agent for treating mild–moderate Crohn’s disease involving the ileum or right colon. Budesonide is a more potent glucocorticoid than prednisolone, but has a hepatic first-pass metabolism of 90% such that only 10% reaches the systemic circulation;

thus, steroid side effects are greatly minimized.¹² When administered for 8–12 weeks at a dose of 9 mg/day, budesonide led to a higher remission rate than mesalamine, 4 g/day (69% versus 45%), but when compared with conventional corticosteroids the results are conflicting.¹³ In a recent metaanalysis of trials comparing budesonide to conventional corticosteroids, budesonide was slightly less effective than prednisone, but was associated with significantly fewer steroid side effects. For a subgroup of patients with ileocecal disease, however, budesonide induced remission in 65%–75% of patients.¹²

Regardless of the treatment strategy chosen, response to therapy should be evaluated after several weeks; 8–16 weeks of therapy may be needed for maximal benefits. Patients achieving remission should be considered for maintenance treatment; treatment failures should be offered an alternative first-line therapy or considered for treatment options offered to patients with moderate–severe Crohn’s disease.

Moderate–Severe Crohn’s Disease

Patients with moderate–severe Crohn’s disease have either failed therapy for mild–moderate disease, or have significant systemic toxicity symptoms including fever, weight loss of

>10%, abdominal pain and tenderness, nausea and vomiting without bowel obstruction, or significant anemia.⁴The treatment options for these patients include corticosteroids (prednisone or budesonide), infliximab, and at a relatively early stage, immunomodulator therapy with either thiopurines or methotrexate. Antibiotics may also be used for moderate–

severe disease, but only for infectious complications such as abscesses, fistulae, or when used in conjunction with surgical drainage procedures. In patients for whom steroids are either ineffective or contraindicated, infusions of infliximab can provide an alternative therapy.

Corticosteroids are the mainstay of therapy in moderate–

severe Crohn’s disease and clinical trials with prednisone at doses of 40–60 mg daily for 8–12 weeks have achieved remission in 50%–70% of patients.⁵In clinical practice, prednisone is usually initiated at 40 mg daily and is continued at this dose until remission has been achieved—usually within 7–28 days.

Subsequently, prednisone is tapered by 5–10 mg weekly until

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patients are on 20 mg, and then by 2.5–5 mg weekly from 20 mg until it is discontinued.¹⁴

Corticosteroids are neither safe nor effective as maintenance therapy¹⁵ and therefore, once steroids are initiated, maintenance strategies must be simultaneously devised. In patients with moderately severe ileal or ileocolonic Crohn’s disease, budesonide 9 mg daily is an effective first-line alternative to prednisone. Treatment failures are usually switched to a conventional corticosteroid.

More than 50% of patients with moderate–severe Crohn’s disease who are initially treated with steroids will become steroid dependent or steroid resistant, and may require therapy with an immunomodulator. Patients who smoke and those with colonic disease are particularly at risk; adjunctive treatment strategies usually are needed.¹⁶No demonstrable benefit has been shown in these patients when combining 5-ASA therapy with steroid therapy.¹⁷

In recent years, steroid-dependent or refractory patients have been treated with the thiopurines—azathioprine (AZA) (2–2.5 mg/kg daily) or 6-mercaptopurine (6-MP) (1–1.5 mg/kg daily), although dose-response studies for these agents have not been performed.¹⁸Recently, genetic polymor- phisms of thiopurine methyltransferase, the primary enzyme metabolizing 6-MP, have been identified that may allow clinicians to more accurately monitor and dose these medications according to measurements of the metabolites 6-thioguanine and 6-methylmercaptopurine.¹⁹Prospective studies to assess the value of this therapeutic monitoring have not been performed.²⁰ The use of thiopurines in moderate–severe active Crohn’s disease is limited by their slow onset of action—3–4 months; however, their addition to steroid therapy has been shown to increase remission rates and to allow steroid-sparing.¹⁸Patients on thiopurines require regular complete blood counts to monitor for leukopenia; these should be performed every 1–2 weeks initially, and then every 3 months once doses are stabilized. Despite previous concerns, there is no increased risk of lymphoproliferative disorders with the thiopurines and they are considered safe during pregnancy.²¹

Parenteral methotrexate, in a dose of 25 mg weekly either subcutaneously or intramuscularly, is an alternative steroid- sparing agent for patients with moderate–severe Crohn’s disease. Parenteral methotrexate has been shown to induce remissions and to be steroid sparing.²²Nausea and asymptomatic mild increases of liver function tests are the most frequently encountered side effects; more serious side effects such as leukopenia and hypersensitivity pneumonitis are seen only rarely. Patients taking methotrexate should be counseled to avoid alcohol, and this drug is absolutely contraindicated in pregnancy.

Infliximab is a chimeric monoclonal antibody to tumor necrosis factor, and is indicated for the induction and maintenance of moderate–severe Crohn’s disease patients who are not responding to corticosteroids and immunomodulators.²³ Infliximab is also effective at reducing the number of draining fistulae in patients with fistulizing Crohn’s disease.²⁴

Emerging indications for infliximab include maintenance therapy for luminal²⁵and fistulizing disease,²⁶steroid-sparing in steroid-dependent patients, early use in hospitalized patients when rapid amelioration of symptoms is desired, and to curtail some of the extraintestinal manifestations of Crohn’s disease.²⁷

Generally, infliximab is started at 5 mg/kg for both induction and maintenance therapy of moderate–severe Crohn’s disease; some patients in the maintenance phase may require an increased dose of 10 mg/kg. A three-dose induction regimen of infliximab given at 0, 2, and 6 weeks has been found to be the optimal dosing strategy for several reasons.²⁸First, a three-dose induction regimen is at least as good as, if not superior to, a single-dose induction regimen. Second, a three- dose induction regimen may be beneficial and allow patients to develop an immunologic tolerance to infliximab. As a result, this regimen may reduce the formation of antibodies to infliximab (previously known as human anti-chimeric antibodies—HACA), and reduce subsequent acute infusion reactions or delayed hypersensitivity reactions, both of which are at least in part related to these antibodies. In the United States, the FDA-approved recommended dose is 5 mg/kg given at 0, 2, and 6 weeks as an induction regimen. Reinfusion every 8 weeks is necessary to maintain response in most patients and is recommended to help reduce the formation of antibodies to infliximab.

Concurrent immunomodulator therapy with AZA, 6-MP, or methotrexate may also improve outcome by reducing the formation of antibodies to infliximab or reducing the incidence of acute infusion reactions or delayed hypersensitivity reactions; most evidence to support this hypothesis is only anecdotal. Given the risk of reactivation of latent tuberculosis, all patients should be screened for tuberculosis with tuber- culin skin testing (and chest X-ray if skin testing is positive) before initiating therapy with infliximab.²⁷

Severe–Fulminant Crohn’s Disease

Patients with severe or fulminant Crohn’s disease have ongo- ing symptoms despite oral steroids or infliximab given as an outpatient and present with high fever, cachexia, persistent vomiting, or may have evidence of an intestinal obstruction or an abscess. These patients almost always require hospital admission and resuscitation with intravenous fluids. Patients with clinical signs of a bowel obstruction or an abscess require an urgent surgical consultation, and intravenous antibiotics should be administered immediately, especially if sepsis is suspected. If sepsis can be excluded, then high-dose intravenous steroids should be started at doses equivalent to 40–60 mg of prednisone by either divided doses or continuous infusion. If patients do not respond to steroids within 5–7 days, alternative therapies such as infliximab, cyclosporine (CSA), or tacrolimus can be considered.

Currently, there is no evidence base to support the use of these agents in this setting other than anecdotal experience.

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Responders to parenteral steroids or CSA are then transitioned to an equivalent oral dose, whereas those failing medical treatments require surgery.⁴

Management of Perianal Crohn’s Disease

Perianal complications of Crohn’s disease include ischiorec- tal abscesses and perianal fistulae, and often require surgical intervention.²⁹ Abscesses require surgical drainage with or without the placement of setons, whereas fistulae should be treated at least initially with medical therapy including antibiotics, immunomodulators, or infliximab. Asymptomatic, nondraining fistulae can be safely observed without treatment once coexisting sepsis has been excluded. Initial medical treatment of abscesses should be with the antibiotics metronidazole or ciprofloxacin. Metronidazole in doses of 10–20 mg/kg is effective in reducing or stopping fistula drainage, although it seems that continuous therapy is needed to avoid recurrence, and side effects may be troublesome, especially peripheral neuropathy. In such cases, ciprofloxacin 500 mg per os twice a day is a reasonable alternative, or the two antibiotics can be given as combination therapy.^30,31

The next line of treatment for perianal disease should be with an immunosuppressant agent such as AZA, 6-MP, CSA, or tacrolimus. Steroids have no role in perianal Crohn’s disease. There are no long-term controlled trials assessing the thiopurines for perianal disease, although anecdotal success has been reported in some 40%–50% patients. Intravenous CSA is particularly potent; however, symptoms recur as soon as patients are begun on oral CSA.³²Similarly, oral tacrolimus is effective, but is also associated with significant nephrotoxicity at effective doses.³³

The role of infliximab in perianal Crohn’s disease deserves special mention. In a placebo-controlled trial, patients who had previously not responded to antibiotics, steroids, or immunomodulators were given 5 mg/kg infliximab at 0, 2, and 6 weeks. Of these patients, 68% had a positive clinical response defined as a reduction by half the number of draining fistulae, and 55% had cessation of draining of all fistulae. The average duration of closure of fistulae was 12 weeks,²⁴ although maintenance therapy to prevent recurrent drainage or abscess has been demonstrated to be efficacious in the same manner as for luminal disease.²⁶Patients receiving infliximab for perianal fistulae may benefit from tempo- rary setons to ensure that recurrent abscess formation is prevented.

Maintenance Therapy for Crohn’s Disease

Once remission has been achieved, the aim of therapy must now turn to maintaining this symptomatic improvement.

Whereas corticosteroid therapy is successful in inducing remission in the majority of patients, it has no role as maintenance therapy in Crohn’s disease, and carries the risk of steroid dependence.¹⁵

After a medically induced remission with corticosteroids, there is no evidence that aminosalicylates are effective in maintaining remission, unlike in UC.¹⁷In contrast, the thiopurines—AZA (2–2.5 mg/kg) and 6-MP (1–1.5 mg/kg)—have been proven to be steroid sparing and to maintain medically induced remission.³⁴Although the optimal dose and duration of therapy are yet to be defined, maintenance benefits have been proven for up to 4 years of therapy.³⁵For patients who have responded to 25 mg/week methotrexate as induction therapy, maintenance benefits using a lower dose of 15 mg/week have been demonstrated, with almost two-thirds of patients maintaining a steroid-free remission at 1 year.³⁶ Patients on either the thiopurines or methotrexate require regular monitoring of blood counts and liver enzymes³⁷; hence, only reliably compliant patients should be chosen for these therapies. The evidence base for maintenance infliximab therapy is rapidly expanding. In a large, multicenter randomized, controlled trial involving 573 patients, those patients receiving 5 or 10 mg/kg infliximab every 8 weeks after a three-dose induction regimen at 0, 2, and 6 weeks were more likely to maintain a steroid-free remission at 30 and 54 weeks than those who did not receive maintenance infliximab therapy.²⁵

Indications for Surgery in Crohn’s Disease

Unlike UC, surgery for Crohn’s disease is not curative, and yet is required in up to two-thirds of patients at some stage of their course to improve symptoms and quality of life. The most common indications for surgery are medically refractory disease, to avoid medication side-effects, or to treat complications of disease such as hemorrhage, perforation, obstruction, or abscess.⁴Although surgical resection is usually done, the disease predictably recurs at the anastomotic site, and stricturoplasty is a reasonable surgical alternative if previous small bowel resections place the patient at risk of short bowel syndrome. Any patient who fails to respond to 7–10 days of intensive inpatient management should be strongly considered for surgery. (See Chapter 42 for surgical management of Crohn’s disease).

Postoperative Prophylaxis for Crohn’s Disease

Postoperative disease recurrence at 1 year after first resection for Crohn’s disease is seen endoscopically in 60%–80% of patients and clinically in 10%–20%, with smoking being the strongest predictive factor for recurrence.³⁸ Luminal factors also seem to be responsible for disease recurrence, as fecal diversion prevents recurrence, only for it to recur once conti- nuity is reestablished.³⁹ Hence, there has been increasing interest in medical therapies given postoperatively to delay disease recurrence.⁴⁰Most studies are small and short-term, and have given conflicting results. Aminosalicylates and metronidazole have both been proven to reduce postoperative recurrence in certain subgroups of patients, particularly those with isolated ileal disease. A metaanalysis of six trials

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evaluating mesalamine at various doses for this purpose showed that the risk reduction for endoscopic recurrence was 18% and for clinical recurrence was 10%, although no dose response was established.⁴¹Metronidazole (20 mg/kg) given for just 3 months from the time of ileal resection reduced clinical relapse versus placebo at 1 year from 25% to 4%, although many patients would have difficulty managing such high doses of the drug for longer periods.^2,42 Similarly, ornidazole administered for 12 months can also reduce endoscopic and clinical recurrences but, unfortunately, also is poorly tolerated by many patients. More recently, giving 6-MP 50 mg daily has been shown to be more effective than either mesalamine or placebo at reducing relapse; larger trials are needed to further validate these results.⁴³

Thus, at present, there are no consistent recommendations regarding medical therapy after surgical resection for Crohn’s disease. Many patients with longstanding strictures have a good postoperative prognosis, whereas patients with rapid progression of perforating complications and smokers have a worse prognosis. All patients should be advised to stop smoking. The choice of a specific postoperative recommendation requires some estimate of the patient’s risk of recurrence as well as a thorough discussion with the patient regarding risks and benefits of medical therapy attempting to reduce the risk of clinical disease recurrence.

Medical Management of UC

In contrast to Crohn’s disease, UC is characterized by diffuse mucosal inflammation that is limited to the colon. It invari- ably affects the rectum, and may extend proximally in a diffuse, continuous, circumferential pattern to involve part or all of the large intestine. The incidence is estimated at 2–14/100,000 person-years, affecting approximately 690,000 individuals in the United States, with a peak incidence in the third decade of life.¹

This section will discuss the induction and maintenance phases of medical treatments for UC, with therapeutic strategies organized according to disease severity. Similar to Crohn’s disease, the clinical goals for UC are to induce and maintain remission. The anatomic extent and clinical severity of disease help guide the therapeutic approach.

Induction Therapy for UC

Patients with UC typically present with bloody diarrhea, rectal urgency, and tenesmus. The primary goal of therapy is to induce clinical remission and promote mucosal healing.¹⁴ Clinical remission is achieved when the inflammatory symptoms of diarrhea, bleeding, passage of mucopus, tenesmus, and urgency resolve, and with patients’ renewed ability to dis- tinguish gas from feces. In endoscopic remission, there is regeneration of an intact mucosa with a visible submucosal vascular pattern, without ulceration, significant friability, or

granularity. Pseudopolyps, mucosal bridging, and areas of

“atrophic mucosa” with distorted vasculature represent previous episodes of severe inflammation. Histologically, remission is characterized by the absence of neutrophils in the epithelial crypts, although it is not customary to perform biopsies to confirm histologic remission.⁴⁴

Clinical remission usually precedes endoscopic healing, which usually precedes histologic remission. To successfully begin maintenance therapy, it is imperative to achieve clinical remission; failure to do so virtually guarantees a relapse, with the need to reinstitute intensive and sometimes more aggres- sive inductive treatment. It has also been demonstrated that failure to achieve endoscopic remission and the presence of residual polymorphonuclear leukocytes in the epithelial crypts are predictors of disease relapse.⁴⁵

Therapies for inducing remission are based on the anatomic extent of disease and clinical severity. Proctitis and distal colitis refer to inflammation limited to below the splenic flexure, and thus amendable to the reach of topical and oral therapy. In extensive disease, the inflammation extends proximal to the splenic flexure and requires systemic medication.

Supplementary topical therapy is often beneficial to treat prominent rectal symptoms of urgency or tenesmus. Disease severity is classified as mild, moderate, severe, or fulminant.

Patients with mild disease have less than four stools daily, with or without blood, no systemic signs of toxicity, and a normal ESR. Moderate disease is characterized by features of both mild and severe disease. Severe disease is characterized by more than six bloody stools per day, abdominal tenderness with signs of systemic toxicity including fever (> 37.5°C), tachycardia (> 90/minute), anemia (< 75% of normal value), and an increased ESR (>30 mm/hour). Fulminant colitis is manifested by more that 10 bloody stools per day, anemia requiring transfusion, signs of systemic toxicity, abdominal distension, and tenderness.⁴⁶For patients with mild–moderate UC, oral and/or topical mesalamine is the mainstay of therapy, whereas topical corticosteroids may be useful in those with distal disease. Oral corticosteroids are reserved for those with moderate–severe disease and for those who did not respond to optimized doses of oral 5-ASA and topical therapies. Patients with severe colitis or those refractory to maximal oral and topical doses of corticosteroids and 5-ASA should be treated with intravenous corticosteroids. Failure to show significant improvement with intravenous corticosteroids is an indication for intravenous CSA, infliximab or a curative colectomy.

Mild–Moderate Proctitis

From a management standpoint, it is best to separate patients with proctitis from those with distal colitis. Although both are amendable to topical therapy, the choice of a topical pharmacologic agent is guided by the proximal extent of disease. Patients with proctitis have disease limited to the rectum, allowing effective topical therapy with suppositories.

Mesalamine suppositories 1–1.5 g/day (Canasa®) either

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nightly or in divided doses are highly effective for proctitis up to 20 cm, and superior to oral 5-ASA therapy⁴⁷and to topical corticosteroids. The proportion of patients achieving remission increases with the duration of treatment and is not dose dependent. Response is usually seen within 2–3 weeks, with higher response rates (63%–79%) at 4–6 weeks.⁴⁸In patients not responding to rectal mesalamine alone, combination therapy with a topical corticosteroid (foam or enema) is better than either therapy alone.⁴⁹Oral mesalamine may be given to those patients failing topical therapies or as an alternative for those who are unable to tolerate topical therapy, but higher dose reg- imens are usually required. Systemic corticosteroids are rarely required in patients with ulcerative proctitis and should only be reserved for patients with severe or refractory disease.

Mild–Moderate Distal Colitis

Topical 5-ASA is the treatment of choice for patients with distal colitis and achieves higher response rates than topical corticosteroids or oral 5-ASA therapy. Remission rates increase with the duration of therapy (63%–72% after 4 weeks) and are independent of dose; there are no apparent advantages of giving doses greater than 1 g/day.⁴⁸Treatment is initiated with nightly mesalamine enema 4 g/60 mL (Rowasa®) administered at bedtime. Although topical 5-ASA is the most effective therapy for distal colitis, compliance may be difficult.

Generally, mesalamine suppositories are easier to retain because of their smaller volume and more viscous state.

Retention of mesalamine enemas is more difficult and may be associated with leakage and occasional abdominal discom- fort. Mesalamine gel and foam formulations are easier to retain, but are not available in the United States. If enema retention is problematic for patients, loperamide (Imodium®) may be taken before enema administration to reduce rectal urgency and improve anal sphincter tone. Alternatively, initial therapy with mesalamine suppositories will allow for rapid improvement of rectal inflammation and improve ability to retain enemas. Smaller volume enemas (30 mL), that are easier to retain, may also be used to reach the upper rectum, reserving higher volume suspensions (60 mL) for more proximal spread up to the splenic flexure.

If a response is not seen within 2–4 weeks, an additional mesalamine enema or suppository may be added in the morning. Alternatively, combination therapy of mesalamine enemas at night and morning topical corticosteroids [e.g., hydrocortisone foam: 80 mg per application (Cortifoam®), or enema 100 mg/60 mL (Cortenema®)] may be considered, which is superior to either therapy alone.⁵⁰ The systemic bioavailability of rectally administered hydrocortisone approaches 80% because of low first-pass hepatic inactiva- tion, and absorption tends to increase as colonic inflammation is reduced. Therefore, steroid-related side effects may begin to manifest after 2–4 weeks of treatment.

Newer formulations of corticosteroids, such as budesonide, are another therapeutic option to treat mild–moderate distal

colitis. Their high first-pass hepatic metabolism markedly reduces systemic bioavailability, endogenous cortisol suppression,⁵¹and thus reduces the potential for steroid-induced side effects. A metaanalysis showed that budesonide enemas (2 mg/100 mL, Entocort® enema) are as effective and offer an alternative to conventional topical corticosteroids.⁵² 5-ASA enemas have achieved higher clinical remission rates than budesonide enemas although both had similar endoscopic and histologic outcomes.⁵³Because the budesonide enema formulation is not available in the United States, our approach is to add budesonide 2 mg tablet into the mesalamine suspensions for night-time administration. Similarly, a compounding pharmacist can produce a combination of 2 mg budesonide/

500 mg mesalamine suppository for nightly or twice daily use in proctitis.

A small proportion of patients have mesalamine hypersensitivity. They may demonstrate worsening of rectal bleeding and urgency with rectal mesalamine, usually within 3–5 days of administration. In patients with mesalamine hypersensitivity, rectal mesalamine should be discontinued, which usually provides symptomatic relief within 72 hours. Treatment with topical corticosteroids is usually effective in achieving remission in this group of patients.

For patients with mild–moderate colitis who are not responding to topical mesalamine (with or without topical corticosteroid), oral mesalamine may be added as combination therapy and is superior to either oral or topical therapies alone.⁵⁴For those who are unable to tolerate or refuse topical therapy, oral mesalamine is an effective alternative for inducing remission. However, it is not as efficacious as topical therapy because of “right-sided constipation” in patients with distal colitis, resulting in decreased 5-ASA delivery to the diseased left colon. Oral corticosteroids are reserved for patients failing the aforementioned therapy.

Mild–Moderate Extensive UC

When a patient has mild–moderate extensive UC, inflammation extends beyond the reach of topical therapy and oral pharmacologic therapy is required. Oral sulfasalazine or one of the newer 5-ASA formulations is the treatment of choice.

In clinical trials, response rates with oral 5-ASA are similar for patients with distal and extensive colitis. Sulfasalazine achieves remission in 64%–80% of patients, at dosages of 2–6 g/day. There is a dose response for sulfasalazine, with larger doses achieving higher remission rates. Unfortunately, as many as 30%–40% patients are unable to tolerate higher therapeutic doses because of systemic absorption of the sulfapyridine conjugate. Patients on sulfasalazine should also receive daily folic acid (1 mg/day) supplementation because of inhibition of folate absorption.

As mentioned previously, the development of sulfa-free 5-ASA delivery forms have enabled clinicians to deliver larger amounts of the active moiety without the dose-limiting systemic toxicity. Effectiveness of these newer 5-ASA

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formulations to induce remission in mild–moderate extensive UC has been confirmed in a recent metaanalysis.⁵⁵ Clinical improvement or remission can be achieved in as many as 84%

of patients with Asacol® (2.4–4.8 g/day), Salofalk®, Claversal®, Mesasal® (1.5–3 g/day), Pentasa® (2– 4 g/day), olsalazine (1–3 g/day), and balsalazide (6.75 g/day). All of the newer 5-ASA formulations have similar pharmacokinetic profiles, are therapeutically equivalent⁵⁶and have similar efficacy to sulfasalazine when equimolar doses are used (1 g sulfasalazine = 400 mg mesalamine = 1.125 g balsalazide) and a dose response is similarly observed. Patients who do not respond to the lower therapeutic dose range within a few weeks should receive doses at the upper end. Adding topical mesalamine or a topical steroid can be a useful adjunct and can help alleviate troublesome rectal symptoms.

The newer 5-ASA formulations are well tolerated and hypersensitivity reactions are rare. Cases of pneumonitis, pericarditis, pancreatitis, and idiosyncratic nephritis have been reported. About 80% of sulfasalazine-intolerant patients will tolerate mesalamine. Up to 30% of patients on olsalazine have worsening of diarrhea resulting from increased ileal secretion, and this dose-related phenomenon usually improves as the colitis heals. However, mesalamine can rarely cause hypersensitivity colitis, which is manifested by worsening diarrhea when 5-ASA therapy is initiated.

Patients with mild–moderate extensive UC not responding to optimal doses of oral mesalamine (with or without topical mesalamine) and those with more severe but nontoxic systemic symptoms will require the addition of oral corticosteroids.

Prednisone at doses of 40–60 mg/day is usually initiated and is effective within 1–2 weeks. Oral prednisone demonstrates a dose-response effect between 20–60 mg; 60 mg is only modestly more effective than 40 mg at the expense of greater side effects.⁵⁷Once remission has been achieved, the dose can be tapered by 5–10 mg every week until the patient is on 20 mg, and then tapered by 2.5–5 mg every week thereafter, while maintaining remission with 5-ASA therapy.

Severe UC

Patients with severe colitis that is refractory to maximal oral treatment with prednisone, 5-ASA, and topical medications should be hospitalized for further management. Initial patient evaluation should include blood tests for hematology, a meta- bolic panel, and total cholesterol level. An infectious process should be ruled out by stool analysis for ova, parasites, and Clostridium difficile toxin, fecal culture and sensitivity, and a rectal biopsy for cytomegalovirus.⁵⁸ Indiscriminate use of nonsteroidal antiinflammatory drugs (NSAIDs), anticholiner- gic agents, and antimotility (e.g., loperamide, diphenoxylate) should be avoided because of the potential of worsening colitis or inducing toxic megacolon.

The mainstay of treatment for severe colitis is parenteral corticosteroids in daily doses equivalent to 300 mg hydrocortisone or 48 mg methylprednisolone. There seems to be no

added benefit to using higher daily doses of steroids. Rectal corticosteroids may be added as adjunctive therapy for those who are able to tolerate and retain enemas, although no controlled studies have confirmed any incremental benefit. There are no data concerning the efficacy of 5-ASA in severe colitis and these may be discontinued, particularly in patients who were recently started on this therapy.

In the original Oxford experience, patients were treated with bowel rest, IV steroids, antibiotics, and rectal steroids for 5–7 days, and then assessed for response. Bowel rest and total parenteral nutrition (TPN) alone have minimal benefit as primary therapy for acute severe UC.⁵⁹ Nutritional support should be provided for severely malnourished patients with the recognition that enteral nutrition has the benefit of fewer complications compared with TPN. If patients are nauseated or vomiting, parenteral nutrition may be required. The routine use of antibiotics has been shown to have no primary, therapeutic benefit in the treatment of severe UC; however, most experienced centers administer broad-spectrum antibiotics to patients with fulminant or anticipated transmural disease.^60,61 Patients with signs of transmural and fulminant colitis (fever, leukocytosis, abdominal tenderness, “thumbprinting”

on abdominal radiograph) who are at risk of toxic megacolon and perforation should be placed on bowel rest and started on broad-spectrum antibiotics. Abdominal radiograph should be done to assess for colonic dilation and to look for free air.

Narcotics and anticholinergics, which may worsen colonic atony and dilation, must be avoided. Because the failure rate of medical therapy in hospitalized severe UC patients approaches 40%, they should also be followed closely by an experienced surgeon. Patients failing to respond to 7 days of intravenous corticosteroids are unlikely to benefit from pro- longing this treatment and should either be considered for intravenous CSA or referred for surgery.⁶²

Patients with toxic megacolon are managed as above. In addition, the gastrointestinal tract should be decompressed with the insertion of a nasogastric tube and a rectal tube.

Other maneuvers, such as assisting the patient to roll from a supine to prone position every 2 hours and a knee-elbow position, may help redistribute gas to the distal colon and rectum, and aid in the expulsion of bowel gas. These patients should be monitored closely in the intensive care unit for any signs of deterioration. Serial abdominal radiographs are usually reviewed every 12 hours and electrolyte abnormalities, such as hypokalemia that may aggravate colonic dysmotility, are treated aggressively. Medical therapy may avoid the need for surgery in up to two-thirds of patient cases.⁶³ Failure to improve within 72 hours is an indication for surgery; any clinical, laboratory, or radiologic deterioration on medical therapy mandates an immediate colectomy.

Intravenous CSA is an effective “rescue” therapy for severe steroid-refractory UC and acts as a bridge to maintenance therapy with the slower-acting thiopurines, AZA or 6-MP.⁶⁴ Patients who are noncompliant, have a history of inadequately controlled seizures or active infection should not be treated

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with CSA. Hypocholesterolemia (serum cholesterol < 120 mg/dL) and hypomagnesemia (serum magnesium < 1.5 mg/dL) significantly increase the risk of seizures in patients treated with CSA. Whereas hypomagnesemia can be cor- rected promptly, cholesterol levels are far more difficult to correct, and should be checked early in potential candidates for intravenous CSA.

Before initiating therapy, the risks and benefits of CSA therapy should be reviewed in detail with the patient and an introductory meeting with the surgeons initiated. While con- tinuing intravenous steroids, CSA is started as a continuous infusion of 2–4 mg/kg daily. A recent study confirmed the efficacy of low-dose CSA, which improves its toxicity pro- file.⁶⁵CSA serum levels are obtained every 48 hours, with a target therapeutic level of 200–400 ng/mL [measured via high-performance liquid chromatography (HPLC)]. Daily inquiries should be made regarding symptoms of CSA toxicity such as paraesthesia, tremors, headache, and nausea.

Blood pressure must be monitored and hypertension adequately controlled with a calcium channel blocker. Serum electrolytes are also monitored for CSA-induced nephrotoxicity, hyperkalemia, and hypomagnesemia, and careful atten- tion given to any evidence of infection, especially at central venous catheter sites. Clinical improvement is generally seen within 4–5 days of initiating CSA treatment. Patients who have not demonstrated a significant improvement within 7 days of intravenous CSA therapy, or whose condition dete- riorates during CSA therapy, are candidates for surgery.⁶⁶

Most recently, infliximab has been used in patients with refractory⁶⁷or steroid-resistant⁶⁸UC. Two large trials, ACT I and ACT 2, have demonstrated efficacy of infliximab dosed at 5 mg/kg at 0, 2, 6 weeks and then every 8 weeks in moderate–severe UC (Sandborn and Rutgeerts, in press) and as a single dose for severe UC to prevent colectomy (Janerot, in press). The ultimate positioning of infliximab for UC remains to be determined.

Maintenance Therapy for UC

The second goal of therapy in UC is to sustain the symptomatic improvement of a clinical remission. Clinical remission is achieved when the following inflammatory symptoms resolve: diarrhea, bleeding, passage of mucopus, tenesmus, and urgency. Endoscopic remission implies maintenance of an intact mucosa without ulceration, friability, or granularity and histologic remission presumes the absence of neutrophils in the epithelial crypts. It has been demonstrated that up to 40% of symptom-free patients had an abnormal sigmoidoscopy and 90% had microscopic inflammatory activity.⁶⁹

Aminosalicylates are the primary maintenance therapy to prevent relapse of remitted UC.⁷⁰AZA and 6-MP are useful steroid-sparing agents for steroid-dependent patients and for maintaining remission in those patients not adequately sustained by 5-ASA alone.⁵⁷Corticosteroids, methotrexate, and nicotine are ineffective maintenance agents. Prolonged

administration of CSA at a dosage of more than 5 mg/kg daily is not advisable because of the risk of nephrotoxicity and, hence, has no role as maintenance therapy.⁷¹

Patients experiencing their first episode of proctitis that has responded promptly to topical treatment may not need maintenance medication as long-term remission may persist. If relapse does occur, there is usually a rapid response to re- treatment. Rarely, patients with a mild first episode of extensive colitis may opt to be followed without maintenance medication although the vast majority of patients will require therapy to prevent relapse.^57,71

5-ASA–induced Remission of UC

Remission can be maintained with oral and/or topical 5-ASA formulations alone after induction therapy for mild–moderate UC. Once remission is attained, topical 5-ASA is the most effective maintenance therapy to prevent relapse of distal disease. Mesalamine suppositories (1–1.5 g/day) and enemas (1–4 g daily) are effective for patients with proctitis and distal colitis, respectively. A dose response is not seen above 1 g/daily in distal disease; however, the frequency of administration is of primary importance.⁴⁸ An attempt is usually made to reduce the frequency of topical therapy: initially every night,³⁶then every other night, then every third night.⁷² Most patients can continue on the lowest frequency of topical therapy that maintains remission and quality of life. The practice of alternate night dosing or every third night dosing does not substantially decrease remission maintenance rates.⁴⁸ Patients who flare after a period of quiescence maintained on mesalamine suppositories may have disease extension.⁷³ These patients will require repeat endoscopy and if extension of colitis is documented, oral therapy will be required.

Oral maintenance therapy for distal colitis is less effective than topical; however, most patients still prefer an oral aminosalicylate for its convenience, and transitioning to an oral maintenance regimen can be attempted. Patients requiring a combination of oral and topical 5-ASA to achieve remission often require combination 5-ASA therapy to maintain remission. An attempt to reduce and taper off rectal mesalamine may be made, but patients who require topical therapy to improve will usually require some regular administration of topical therapy to maintain remission. One study suggested that combination therapy with oral and inter- mittent rectal mesalamine (twice a week) is better than oral therapy alone.⁷⁴

An oral aminosalicylate is the primary maintenance therapy for extensive colitis. A recent Cochrane review affirmed its efficacy as maintenance therapy in UC.⁷⁰In contrast to topical 5-ASA, there is a dose-dependent efficacy in the maintenance effects of all oral 5-ASA. However, sulfasalazine is often limited by its dose-dependent adverse effects and although the optimal maintenance dose was determined to be 4 g/day, dose reduction to the lower 2 g/day is recommended to best balance sulfasalazine’s efficacy and side effects.

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There is currently no evidence to suggest that the newer 5-ASA formulations are more effective than sulfasalazine, but they have markedly lower incidence of adverse events, allowing a clinical response with an oral dose of up to 4.8 g/day without increasing toxicity. In the absence of an extensive evidence base for dosing mesalamine maintenance therapy, it has been our experience that the optimal maintenance dose is the same dose required to induce remission. We also administer oral therapy with aminosalicylates on a twice-daily schedule to improve compliance. Adherence to therapy is critical to an optimal long-term outcome, because patients who take less than 80% of the prescribed 5-ASA have a fivefold increase in the risk of relapse.⁷⁵Risk factors for poor adherence include being single, being of the male gender, and use of multiple medications.⁷⁶

Steroid-induced Remission in UC

Corticosteroids (oral or topical) are ineffective maintenance agents and should be tapered and weaned off once remission has been achieved. 5-ASA remains the primary maintenance therapy after a steroid-induced remission, but will usually require higher doses equivalent to 2.4–4.8 g of mesalamine daily. Approximately one-fifth of patients that were treated with corticosteroids are steroid-dependent at 1 year⁷⁷; these patients typically experience a relapse of symptoms when corticosteroids are tapered below a threshold dose of 15–20 mg/day. Because chronic long-term use of corticosteroids is unacceptable, patients should be considered for long-term immunosuppressive drug therapy with the thiopurines or a curative colectomy. AZA at doses of 2–2.5 mg/kg and 6-MP at doses of 1–1.5 mg/kg daily are effective steroid-sparing^78–80 and maintenance agents^81,82 in up to two-thirds of patients.

The thiopurines have a slow onset of action and, while allowing time for them to take effect, patients are typically maintained on corticosteroids that are gradually tapered in the subsequent 2–3 months.

CSA-induced Remission in UC

Steroid-refractory patients achieving remission with intravenous CSA are transitioned to oral CSA. The usual prescribed oral dose is twice the daily intravenous dose. In addition to oral prednisone 40–60 mg/day, AZA (2–2.5 mg/kg/day), or 6-MP (1–1.5 mg/kg/day) is initiated before discharge. Long-term outcome studies have demonstrated the importance of maintenance therapy with AZA or 6-MP that will allow more than half of severe, steroid-refractory UC patients to avoid surgery in the long term after a CSA-induced remission.^83,84Because of the risk of opportunistic infection during the period of triple immunosuppressive therapy, Pneumocystis carinii prophylaxis with one double-strength trimethoprim-sulfamethoxazole tablet taken 3 times weekly is now standard therapy. Patients are followed up closely with the goal of maintaining CSA blood trough levels in the range of 150–300 ng/mL (HPLC). Corticosteroids are gradually

tapered within the ensuing 3 months and once adequate time (usually 3 months) has been allowed for the effect of AZA or 6-MP to “kick in,” CSA is tapered by reducing the dose by 50% for 2 weeks followed by complete withdrawal. A patient who relapses while on drug taper will usually be referred for surgery.

Refractory UC Disease

Some patients continue to have active inflammatory disease despite maximal medical therapy with 5-ASA and steroids, yet are not so acutely ill as to warrant hospitalization for intravenous steroids and/or CSA or surgery. Conditions con- tributing to refractoriness must be excluded: treatment nonad- herence, concurrent use of NSAIDs, infection, and 5-ASA hypersensitivity. Concomitant irritable bowel syndrome (IBS) may masquerade as “refractory” disease; the absence of inflammatory symptoms (urgency, rectal bleeding, fever), the prominence of abdominal bloating and cramping, and a normal flexible sigmoidoscopy aid in the diagnosis of IBS.

Uncontrolled series have demonstrated the value of AZA and 6-MP in achieving remission in these steroid refractory, chronically active UC patients.^80,82,85 It is anticipated that infliximab will become an alternative option for this subgroup of patients who do not tolerate or respond to AZA or 6-MP.

Colectomy may be the final option in these patients.

Indications for Surgery in UC

Between 30%–40% of UC patients will eventually require surgery, with the majority of patients requiring surgery within 10 years of initial diagnosis. Emergent surgery is indicated when there is massive hemorrhage, toxic megacolon, perforation, and severe colitis that is unresponsive to medical therapy. Elective surgery is indicated for those with cancer or dysplasia, failure of or suffering from complications of medical therapy, and rarely to correct malnutrition and growth retardation in children, and to control debilitating extraintestinal manifestations. Chapter 41 discusses the surgical management of UC.

Conclusion

The medical therapy of IBD is a complex and challenging area that requires close collaboration between the patient, gastroen- terologist, and surgeon. The concepts or therapeutic goals of first inducing and then maintaining remission are important to understand, and different agents are used to achieve these goals in both Crohn’s disease and UC, albeit with considerable overlap. Corticosteroids are successful at inducing remission in both diseases, but they have no role as maintenance agents, and steroid-sparing agents such as AZA or 6-MP, or methotrexate in the case of Crohn’s disease, should be added at the first sign of steroid-dependence. Infliximab is now well