Inflammatory Bowel Disease Treatment & Management

The two goals of therapy are the achievement of remission (induction) and the prevention of disease flares (maintenance). Note that a top-down approach, with earlier introduction of biologics and immunomodulators, is frequently advocated to forestall complications. ^[76]

The care of a patient with inflammatory bowel disease (IBD) can be either medical or surgical in nature or, in many patients, a combination of both. The management algorithm is also dependent on whether the diagnosis is Crohn disease or ulcerative colitis. The medical approach for patients with IBD is both symptomatic care (ie, relief of symptoms) and mucosal healing. Mild disease can follow a stepwise approach to medication, with escalation of the medical regimen until a response is achieved. More moderate to severe disease, however, warrants more aggressive initial treatment for the prevention of intestinal complications.

The concept of deep mucosal healing, particularly in Crohn disease, is becoming routine care. There are several studies, primarily involving anti-TNF agents (and occasionally immune modifiers); that have shown that the elimination of inflammation (as demonstrated by endoscopic and histologic criteria) results in a decrease in the rate of surgery, the use of corticosteroids, and the rate of hospitalization. ^{[77, 78, 79, 80, 81, 82, 83]} This supports the use of immune-modifying agents (mercaptopurine or azathioprine) or one of the anti-TNF agents earlier in the course of IBD. ^{[77, 78, 79, 80, 81, 82, 83]}

Symptomatic therapy

In addition to treatment of the underlying inflammation, patients with inflammatory bowel disease (IBD) may require symptomatic therapy, particularly when their symptoms are not related to active inflammation. Treatment with antidiarrheal agents such as loperamide or diphenoxylate/atropine should generally be avoided in patients with active inflammation, as these drugs can precipitate toxic megacolon in individuals with significant colonic inflammation. Similarly, other agents that may have anticholinergic effects should be avoided, although antispasmodic medications may sometimes be useful for symptomatic relief. In patients with Crohn disease who have significant ileal disease or who have had an ileal resection, diarrhea may sometimes be due to bile salt malabsorption. In such patients, treatment with bile-binding resins, such as cholestyramine, may be helpful in managing the diarrhea.

Supportive care

IBD flares in patients with mild to moderate disease are usually managed in an outpatient setting. However, an important and sometimes overlooked concern in the management of IBD is the dosing and duration of the use of corticosteroid therapy. For a flare of moderate severity, a dose of prednisone of 20-40 mg/day or equivalent is often sufficient to treat the flares. Once symptoms are controlled, a dedicated tapering of the steroid dose follows.

Patients are candidates for immunomodulators (azathioprine, 6-mercaptopurine, methotrexate) or anti-TNF agents (infliximab, adalimumab, certolizumab pegol) and biologic agents if flares are frequent (>1-2 times), if the duration of steroid use is prolonged (more than a few weeks per year), if reduction of the steroid dose causes recurrence of symptoms (steroid dependent), or if steroids do not appear to be working (steroid refractory).

A subset of patients (pediatric patients with Crohn disease [not ulcerative colitis]) has been shown to benefit from the use of exclusive enteral nutrition (EEN); in many parts of the world this is used prior to other forms of treatment. EEN can produce remission rates as high as 60%-80% in this population, although significant mucosal healing and significant longevity of remission have not been demonstrated. EEN uses elemental or polymeric feeding formulae that can be consumed by mouth but is often administered by nasoenteric feeding tube, generally at night. It has not been well studied in adult populations; the taste of the formulae, the large quantity required to meet nutritional needs, and the adverse impact on quality of life are all inhibitors to its use in the adult population. ^[84]

A health maintenance issue of particular importance to patients with IBD is a reduction in bone density because of decreased calcium absorption (due to the underlying disease process) or corticosteroid use. Osteoporosis is a very serious complication, involving 40% of patients with IBD, and increases the risk for fractures. All patients who have been using steroids for longer than 3 months, as well as postmenopausal women, should undergo testing with bone-density studies; treatment with bisphosphonates and calcium supplements can be initiated in patients with significantly low bone density.

A stepwise approach (now generally referred to as the step-up approach), such as outlined in the following sections, may be taken in mild inflammatory bowel disease (IBD). More moderate to severe IBD should be treated more aggressively up front to prevent permanent damage.

The first step in medication therapy for mild IBD is usually aminosalicylates. There are several different aminosalicylates, but none have been consistently demonstrated to be superior to the others for all patients. These agents appear to have greater efficacy for the treatment of ulcerative colitis than for Crohn disease, for which efficacy data are limited. For Crohn disease, metronidazole or ciprofloxacin is occasionally used, particularly for perianal disease or an inflammatory mass.

If the patient's condition fails to respond to an adequate dose of aminosalicylates, the second step is often corticosteroids, which tend to provide rapid relief of symptoms and a significant decrease in inflammation. ^[85] The most common range for moderate flares of IBD is oral prednisone at 10-40 mg/day; for more severe flares, the higher end of the range is used (occasionally doses up to 60 mg/day). Once a clinical response is seen, the dose is tapered. Most patients who use oral corticosteroids can tolerate a relatively rapid taper after a response is achieved; occasionally, a very prolonged steroid taper is necessary to prevent relapse in patients who have had prolonged exposure to steroids in the past. Inability to taper down the steroids without recurrence of symptoms should trigger discussion regarding the use of alternative drugs (immunomodulators or anti-TNF therapy). The advantage of steroids is that they work quickly and are effective for acute flares; they are not effective for maintenance of remission, however.

The immune-modifying agents are used if corticosteroids fail or are required for prolonged periods for milder disease; they can be used up front for moderate and severe disease. Anti-TNF monoclonal antibody therapies are also effective in both Crohn disease and ulcerative colitis; some studies have demonstrated that they have a greater efficacy than azathioprine. Historically, anti-TNF agents have been administered when Crohn disease has been unresponsive to steroids and immunosuppressants; however, the early introduction of these agents in conjunction with immunosuppressants in those with an increased risk of a complicated, severe, or possibly aggressive IBD has the potential to modify the disease course and is commonly pursued. ^[76]

Drugs from different therapeutic classes may be used additively. In patients with moderate to severe or high-risk disease, a step-down approach with early introduction of stronger agents such as the anti-TNF agents has been advocated to prevent complications and improve patient outcomes. There are many situations, especially in patients with more severe disease, where early use of anti-TNF agents or other biologics is clearly in the patient’s best interest.

In general, one major goal is to wean the patient off steroids as soon as possible to prevent long-term adverse effects from these agents. Ardizzone et al suggest that a lack of mucosal healing after corticosteroid therapy is the only factor associated with negative outcomes at 5 years. ^[86]

The five oral aminosalicylate preparations available for use in the United States are sulfasalazine (Azulfidine), mesalamine (Asacol, Asacol HD, Pentasa, Lialda, Apriso), balsalazide (Colazal), and olsalazine (Dipentum). Enema and suppository formulations are also available. All of these are derivatives of 5-aminosalicylic acid (5-ASA); the major differences are in the mechanism and site of delivery. Some of these agents also have unique adverse effects lacking in other agents of this class.

All of the aminosalicylates are useful for treating flares of IBD and for maintaining remission. None of the aminosalicylates has been proven to have greater efficacy than any of the others for the treatment of ulcerative colitis. As a class, these agents appear to be more effective in persons with ulcerative colitis than in persons with Crohn disease; in persons with mild Crohn disease, the primary utility is for colonic disease (as is the case with sulfasalazine ^[1] ; administer folic acid if sulfasalazine is used). Aminosalicylates have only a weak effect in preventing recurrence after surgery in patients with Crohn disease. ^[87]

For patients in remission from distal ulcerative colitis, oral or rectal 5-ASA can be used to manage this disease, as well as a combination regimen of oral and topical 5-ASA. ^[1] In treating rectal disease, rectal 5-ASA is preferred over rectal steroids. ^[1] A dose response has been described regarding the use of these agents for ulcerative colitis. For moderate disease, a dose of 4.8 g/day of mesalamine has been shown to be more efficacious than 2.4 g/day. ^[88]

Probiotic agents

Supplementation of the high-potency probiotic mixtures (eg, VSL#3 ^{[24, 89, 90]} ) have been shown in some reports to reduce ulcerative colitis disease activity index scores in patients with mild to moderate relapsing ulcerative colitis who are being treated with 5-ASA. Studies in patients with Crohn disease have been much less promising.

The antibiotics metronidazole and ciprofloxacin are the most commonly used antibiotics in persons with inflammatory bowel disease (IBD). According to a systemic review, antituberculosis therapy, macrolides, fluoroquinolones, 5-nitroimidazoles, and rifaximin (alone or in combination) have not consistently been shown to induce remission in selective active Crohn disease and have rarely been shown to induce remission in ulcerative colitis. ^[91]

Antibiotics are used only sparingly in persons with ulcerative colitis because of limited treatment efficacy and because of an increased risk of developing antibiotic-associated pseudomembranous colitis. In persons with Crohn disease, antibiotics are used for various indications, most commonly for perianal disease, fistulas, and intra-abdominal inflammatory masses.

Antibiotics have potential adverse effects, including nausea, anorexia, diarrhea, and monilial (candidal) infections. Peripheral neuropathy can be observed in association with metronidazole and, when present, requires discontinuation of therapy with that drug. Finally, antibiotics can also increase the risk of Clostridium difficile colitis.

Corticosteroids are rapid-acting anti-inflammatory agents used in the treatment of inflammatory bowel disease (IBD). These drugs are indicated for acute flares of disease only and have no role in the maintenance of remission.

Corticosteroids may be administered by various routes depending on the location and severity of disease; they may be administered intravenously (ie, methylprednisolone, hydrocortisone), orally (ie, prednisone, prednisolone, budesonide, dexamethasone), or topically (ie, enema, suppository, or foam preparations).Corticosteroids are limited by their adverse effects, particularly with prolonged use.

The potential complications of corticosteroid use include fluid and electrolyte abnormalities, osteoporosis, avascular bone necrosis, peptic ulcers, cataracts, glaucoma, neurologic and endocrine dysfunctions, infectious complications, and occasional psychiatric disorders (including psychosis).

The consensus regarding treatment with these agents is that they should be tapered once remission has been induced. (see Surgical Intervention for information on Tapering corticosteroids in the postoperative setting). Corticosteroids do not have a role in maintaining remission.

Patients who are concerned about immunosuppressive therapies, including immunomodulators or anti–tumor necrosis factor (TNF) agents, should be educated about the potential greater incidence of complications occurring with long-term steroid use and with undertreated disease. Patients with prolonged use of steroids may also require ophthalmologic examination because of the risk of development of glaucoma and cataracts.

Periodic assessment of bone mineral density is recommended for patients taking steroids for more than 3 months. ^[60] Agents used for osteoporosis prevention and treatment (eg, the bisphosphonates) are useful for preventing the bone loss associated with corticosteroid use.

Intravenous corticosteroids

Intravenous corticosteroids are often used in patients who are severely ill and hospitalized; few data have been published on the optimum dosage of IV or oral corticosteroids. The upper end of dosing generally includes IV methylprednisolone at 20 mg every 8 hours or IV hydrocortisone at 100 mg every 8 hours. Typically, once a clinical response is observed (usually within 3-5 days), the dose of the IV corticosteroid can be tapered. Before hospital discharge, conversion to an oral corticosteroid is made with dosage tapering in an outpatient setting.

Oral corticosteroids

When oral corticosteroids are used, dosing is variable, and few data have been published to guide optimal dosing. The most common range for moderate flares of IBD is prednisone at 10-40 mg/day. For more severe flares, doses up to 60 mg/day may be used, but there are no supportive data. Once a clinical response is seen, the dose is tapered. Most patients who use oral corticosteroids can occasionally tolerate a relatively rapid taper after a response is achieved; a prolonged steroid taper is rarely necessary to prevent relapse. When the latter situation occurs, consider escalation of therapy with the use of alternative drugs (immune modifiers or anti-TNF therapy).

Budesonide (Entocort EC), a synthetic corticosteroid, is available for Crohn disease with ileal or ileocecal involvement. ^[71] Budesonide has extensive first-pass metabolism, which limits systemic adverse effects. ^[60] However, some absorption occurs over a prolonged period of exposure. Budesonide is also less effective than other standard glucocorticosteroids for the treatment of ileal Crohn disease and has not demonstrated efficacy in maintaining therapy beyond 12 months. ^[91]

According to the American Gastroenterological Association (AGA) guidelines, ileal-release preparations of budesonide are indicated for the treatment of patients with mild to moderate ileal and right-sided colonic Crohn disease. ^[60] A newer preparation of budensonide, budesonide MMX 9 mg once daily, has demonstrated efficacy in inducing remission in mild to moderate ulcerative colitis. ^[92]  

Topical corticosteroids

Topical corticosteroids are used in persons with distal colonic disease in a manner similar to that of topical mesalamine; the major difference is that even though topical mesalamine may be used to help maintain remission, topical corticosteroids are used for active disease and have only a small role in the maintenance of remission. According to AGA guidelines, topical therapy with either hydrocortisone (grade A recommendation) or budesonide (grade B recommendation) is effective for distal colonic inflammation in patients with mild to moderate IBD. ^[60]

Patients with ulcerative colitis with predominantly distal disease may be treated with topical budesonide, a synthetic steroid which has local anti-inflammatory effects and limited systemic effects. ^[93] Although topical budesonide is effective, novel oral controlled-release formulations have been developed to enable treatment of the entire colon. ^[93]

Rectal corticosteroids

Cortenema, Cortifoam, and Anusol-HC suppositories, as well as Uceris (budesonide) foam are useful in treating distal disease (proctitis and proctosigmoiditis).

Immune modifiers have a slower onset of action (typically, a 2- to 3-month lag) and, consequently, are not used for induction of remission. However, these agents have shown effectiveness for their steroid-sparing action in persons with refractory disease; they are also used as primary treatment for fistulas and maintenance of remission in patients intolerant of or not responsive to aminosalicylates.

The immunomodulators 6-mercaptopurine (6-MP) and azathioprine (AZA) are used in patients with inflammatory bowel disease (IBD) in whom remission is difficult to maintain with the aminosalicylates alone, or they can be started in patients with more moderate to severe disease whereas steroids are used to induce remission. Calcineurin inhibitors such as cyclosporin A (CSA) and tacrolimus, as well as methotrexate (MTX), are also immune-modifying agents ^[1] ; CSA is almost exclusively limited to acute severe colitis, whereas tacrolimus has been used in both perianal Crohn disease and ulcerative colitis. ^[1]

Data on MTX support the use of intramuscular MTX in Crohn disease, but such data are lacking in ulcerative colitis. Methotrexate has been shown to be ineffective to treat ulcerative colitis. ^[94] Two clinical trials showed that AZA continuation in patients with ulcerative colitis prevented relapse, as compared to those who discontinued the medication. However, other trials have shown trends but no statistically significant benefit of AZA in ulcerative colitis. ^[95]

Thiopurine agents

The American Gastroenterological Association (AGA), in accordance with the US Food and Drug Administration (FDA), recommends that patients undergo assessment of the thiopurine methyltransferase (TPMT) genotype or phenotype before starting therapy with AZA or 6-MP. ^[60] Individuals who have low enzyme activity or are homozygous deficient in the TPMT mutation are at risk of very severe leukopenia, with potential septic complications, and may not be good candidates for therapy with these drugs. ^[60]

About 11% of individuals with heterozygous TPMT activity respond well to therapy but are prone to myelotoxicity, although this can be minimized with the use of lower doses. These patients, as well as those with wild-type TPMT activity, require monitoring for complications. ^[60]

Adverse effects and monitoring

Use of immune modifiers mandates monitoring of blood parameters; they can cause significant neutropenia or pancytopenia that warrants a dose reduction or discontinuation. Routine complete blood cell (CBC) counts with differentials and platelet counts are checked monthly, and liver function tests (LFTs) can be performed intermittently. After a year of stable dosing with no difficulties with blood counts (except the expected lymphopenia), the interval between blood count monitoring can be increased.

The cytopenic effect is typically dose dependent, although some patients are more sensitive than others. The typical AZA dose is 2-2.5 mg/kg/day, whereas the dose of 6-MP is 1-1.5 mg/kg/day. In some studies, blood levels of 6-thioguanine has been shown to guide dosing, but such tests offer little advantage, at a much greater cost for routine monitoring and dose adjustment, over CBC counts and liver function tests. In independent studies, metabolite levels have not shown any correlation with clinical efficacy, but they may help in monitoring compliance.

Other adverse effects of the immune modifiers include fever, rash, infectious complications, hepatitis, pancreatitis, and bone marrow depression. The most common reason for discontinuing the immune modifiers within the first few weeks is the development of abdominal pain; occasionally, a biochemically demonstrable pancreatitis occurs.

Concerns have been raised about the development of malignancy in patients taking 6-MP and azathioprine. These agents have been associated with a 2- to 4-fold greater incidence of lymphoma and an increase in nonmelanoma skin cancers, but curiously, there is a 3.5-fold decrease in colorectal carcinoma. A higher risk is present based on age. ^[96]

Janus kinase (JAK) inhibitor

The oral JAK inhibitor tofacitinib (Xeljanz) has been approved for the treatment of moderate to severe ulcerative colitis. Unpublished studies in the package insert show an induction of remission in 15% to 20% of patients within 8 weeks; at 1 year, maintenance of remission was demonstrated in approximately 35% of patients. The side-effect profile of tofacitinib is very similar to that of mercaptopurine and azathioprine, with the additional concern for elevations of cholesterol. Like the above immune modulators, tofacitinib is associated with an increase in malignancies. Strong inhibitors of CYP3A4 (eg, clarithromycin) can increase serum concentrations of tofacitinib, while inducers of CYP3A4 (eg, rifampin) can decrease serum concentrations of tofacitinib. Tofacitinib should not be used with other biologic agents or with immunosuppressant drugs such as azathioprine or mercaptopurine. Live vaccines should be avoided.

Anti-TNF-alpha monoclonal antibodies

Infliximab

Infliximab (Remicade) is an anti-TNF-alpha monoclonal antibody that is administered by infusion for the treatment of Crohn disease. Infliximab is FDA approved for both ulcerative colitis and Crohn disease; it appears to have a higher efficacy rate in Crohn disease. Infliximab is generally administered as 3 separate infusions of 5 mg/kg for the induction of remission of moderate to severe IBD at weeks 0, 2, and 6, followed by infusions every 8 weeks for maintenance of remission. Vande Casteele et al found that targeting the trough concentrations of infliximab to levels of 3-7 μg/mL results in a more efficient use of this agent in patients with IBD. ^[97]

A systemic review of the efficacy of biologic therapies in IBD confirmed that anti-TNF-alpha agents and natalizumab were effective in inducing remission of active Crohn disease. ^[98] For Crohn disease, the response rate may be as high as 80% (the usual response rate to natalizumab is about 60%), and the induction of remission rate is 30%-50% after a single dose; with multiple dosing, higher rates of remission are attained. For ulcerative colitis, the response rates may be as high as 50%-70%.

Patients with moderate to severe Crohn disease who have documented active inflammation, dependence on corticosteroids and an inability to taper these agents, or disease refractory to steroids are most likely to benefit from anti-TNF therapy. ^[99] Before anti-TNF agents are administered, screening should be done for coexistent infection with perianal and abdominal abscess (including Mycobacterium tuberculosis), and caution is advised if a patient is a carrier for the hepatitis B virus. ^[99]

Cessation of infliximab therapy, even in patients who are in prolonged remission, is associated with high rates of disease flare. In a study of 115 patients with Crohn disease who were treated for a minimum of 1 year with infliximab and an antimetabolite, who had at least 6 months of corticosteroid-free remission, and who subsequently stopped infliximab therapy, 45% (52/115) had a relapse at a median of 28 months’ follow-up, with a 1-year relapse rate of 43.9%. ^[100] Risk factors for relapse included male sex, leukocyte count greater than 6.0 × 10⁹/L, C-reactive protein level of 5.0 mg/L or greater, and a fecal calprotectin level of 300 µg/g or more. Re-treatment with infliximab was successful in 88% of patients who had a relapse. ^[100]

Infliximab is also indicated for the treatment of fistulizing Crohn disease. For this indication, the fistula responds (closes) in 68% of patients treated with infliximab, although 12% may develop an abscess. The response can be maintained by continuing regular dosing (ie, every 8 weeks) after the induction dose.

Adverse effects of infliximab

The adverse effects of infliximab are uncommon but can include hypersensitivity and flulike symptoms; the latter can often be avoided by pretreatment with acetaminophen and diphenhydramine. There have been rare reports of lupus-like reactions and lymphoproliferative malignancies, although whether the malignancies are related to the drug or to the underlying disease process remains uncertain; they are more likely to be due to the concomitant use of immunomodulators.

Adalimumab, certolizumab,golimumab

Other anti-TNF agents include adalimumab (Humira), which is given by subcutaneous (SC) injection every 2 weeks after a loading dose of 6 injections over 4 weeks ^[101] ; certolizumab pegol (Cimzia), which is given by SC injection every 4 weeks (only approved for Crohn diesase); and golimumab (Simponi), which is given by subcutaneous (SC) injection every 4 weeks after two loading doses (only approved for ulcerative colitis).

Natalizumab

Natalizumab (Tysabri), an agent aimed at preventing the accumulation of lymphocytes in the diseased bowel by blocking the effects of both α4β7 integrin (gut specific) and α4β1 integrin (CNS specific), has been approved by the FDA, but it is only available through a restricted distribution program. Natalizumab is an intravenous medication that has shown efficacy in Crohn disease, but there have been three reports of progressive multifocal leukoencephalopathy, a potentially fatal opportunistic viral infection. Risk is typically apparent in those with prior immunosuppressant exposure or with a duration of infusion for longer than 2 years. ^[102] Patients in whom this agent is used should first be tested for John Cunningham (JC) virus, and they should be periodically tested for this during treatment.

Vedolizumab

Vedolizumab (Entyvio), another integrin antagonist, is approved for Crohn disease and ulcerative colitis. ^[103] It is specific for α4β7 integrin. Approval was based on several phase 3 clinical trials that simultaneously evaluated vedolizumab for both ulcerative colitis and Crohn disease and involved patients in nearly 40 countries. Among patients with Crohn disease who had a response to induction therapy with vedolizumab, 39.0% of those assigned to vedolizumab every 8 weeks were in clinical remission at week 52, compared with 21.6% assigned to placebo.

In patients with ulcerative colitis who had a response to vedolizumab induction, 41.8% continued to be in clinical remission at 52 weeks compared with 15.9% of patient taking placebo.

Ustekinemab

Ustekinemab (Stelara) is an antibody that blocks IL-12 and IL-23. It is used in patients with moderate to severe Crohn disease after failure with treatment using other agents. In clinical trials ustekinemab induced a clinical response of 34% by week 6 and remission in 21% by week 8 in patients with previously failed anti-TNF treatment. Results were better in patients who had treatment failure with immunosuppressants and corticosteroids, with response of 56% and remission and 40% at the same time periods. ^[104] Remission was achieved in 53% of patients at 44 weeks. Adverse effects include the common infectious agents seen with other immune inhibitors, as well as occasional cases of a noninfectious interstitial or eosinophilic pneumonia. ^[104] Use of ustekinemab has been demonstrated to decrease hospitalization and requirements for surgery. ^[105]

Clinical trial agents tend to be disease-specific (ie, an agent works for Crohn disease but not for ulcerative colitis, or vice versa). These include anti-adhesion molecules and anticytokine therapies. ^[1] In Crohn disease, additional agents include T-cell marker therapies and mesenchymal stem cells; in ulcerative colitis, anti-inflammatory proteins have also been studied. ^[1]

Patients should be admitted to the hospital if surgical intervention is anticipated or if their condition does not respond to outpatient treatment, if they are dehydrated, or if they have uncontrolled pain or diarrhea. Start IV hydration. If indicated, obtain an abdominal flat-plate image to exclude obstruction or megacolon. If the patient is nauseous or vomiting or has evidence of obstruction or megacolon, nasogastric intubation may be helpful. Consider early consultation with a surgeon in the setting of severe colitis or bowel obstruction.

If the patient has active colitis, send a stool sample for Clostridium difficile toxin assay and routine microbiologic culture. Laboratory studies to be considered include a complete blood cell (CBC) count with differential; erythrocyte sedimentation rate; levels of albumin, glucose, calcium, magnesium, phosphate, and BUN/creatinine; electrolyte status; and a pregnancy test in females of childbearing age.

Patients with acute severe colitis are treated with IV corticosteroids. Antibiotics are not routinely used but may be indicated in select patients. Electrolyte correction and, potentially, blood transfusion can be administered if indicated on the basis of laboratory findings. The IBD Sydney Organisation and the Australian Inflammatory Bowel Diseases Consensus Group recommendations include the following for patients with acute severe ulcerative colitis ^[106] :

• Hospitalization
• Unprepared flexible sigmoidoscopy to assess severity and exclude cytomegalovirus colitis
• Intravenous thromboembolism prophylaxis
• IV hydrocortisone 100 mg tid/qid and close monitoring
• If insufficient response by day 3, initiate rescue therapy with infliximab or cyclosporine
• If no response by day 7 of rescue therapy or if clinical deterioration occurs, consider colectomy

Author information

Patients with suspected bowel obstruction should be given nothing by mouth (NPO), except for medications. Most patients with ulcerative colitis may maintain a regular (or low-fiber) diet, unless megacolon is present or surgery is being contemplated.

Although a colonoscopic evaluation may also be contemplated, consider the increased risk of perforation in persons with acute colitis. Assess and correct the posthydration CBC count and electrolyte levels, as indicated. Depending on the response to the initial interventions, advancement of the diet may be considered.

By the second or third hospital day, most patients should be showing clear evidence of clinical improvement with IV steroids. Assess the electrolyte status if IV fluids are still being administered. Consider advancement of the diet. The corticosteroid dose can be tapered. If the patient is not improving, consider other treatment options; these may include hyperalimentation, other medical therapies, surgical intervention, or transfer to a tertiary care facility.

Continue to advance the diet, as tolerated, on hospital day 4. Continue the switch to oral medications. Many patients with a flare of Crohn disease or ulcerative colitis may be discharged by this time (occasionally even sooner); some may require another day of IV therapy.

If no progress has been made in the patient's condition since admission, additional treatments are necessary, including surgery (see Surgical Intervention, below) or more aggressive medical treatments. Again, consider transfer to a tertiary care facility. If the patient has been unable to tolerate an oral diet, initiate hyperalimentation and/or reconsider surgical intervention.

Most patients should be able to be discharged on or before the fifth hospital day. A regular diet should be tolerated, with some restrictions if strictures are present. An ESR level may be obtained to assist in future disease assessment, but its result is unlikely to alter current management.

Discharge the patient on oral medications, with appropriate follow-up as an outpatient, typically within a few weeks.

Aggressive therapy should be considered early in the management of patients with difficult or refractory inflammatory bowel disease (IBD). This approach uses immune modifiers and/or anti-tumor necrosis factor (TNF) agents earlier in the treatment of the IBD patient (see Overview of Stepwise Therapy).

Immune modifiers

If it is difficult to reduce the dose of corticosteroids, if the disease is refractory to corticosteroid therapy, or if patients are corticosteroid dependent, the use of immune modifiers 6-MP or azathioprine should be used. The typical dosing of 6-MP or azathioprine is 1-2 mg/kg/day. At higher doses, closer monitoring is warranted, including measurement of the thiopurine methyltransferase (TPMT) enzyme; obtaining 6-TG and 6-MMP levels; doing a CBC; and determining liver, kidney, pancreatic functions.

These agents are not used for acute flares, because the time from the initiation of treatment to the onset of significant action may be as long as 2-3 months. Response to immune modifiers may be dose dependent; monitoring of blood counts is required to protect the patient from the hematologic toxicity associated with these agents.

Monoclonal antibodies

An alternative agent is infliximab, a monoclonal antibody against TNF-alpha. The FDA approved infliximab for the treatment of Crohn disease in July 2005 and for the treatment of ulcerative colitis in August 2005. To be effective for maintaining remission, this medication is generally administered in 3 doses of 5 mg/kg over 6 weeks (at weeks 0, 2, and 6), with maintenance doses every 8 weeks.

A randomized, controlled trial demonstrated that adalimumab can induce remission in patients with Crohn disease that is refractory to treatment with infliximab. ^[107] This therapy led to mucosal healing and a reduction in hospitalization and surgical intervention. The rate of serious infection was 2%-4%, which was no greater than the rate in patients receiving placebo. ^[107]

Note that in September 2011, the US Food and Drug Administration (FDA) issued a notification regarding updates to the Black Box Warning for the entire class of tumor necrosis factor (TNF)-alpha blockers. ^[108] The advisory included the risk of Legionella and Listeria infections, as well as consistency of the information in the Boxed Warning and the Warnings and Precautions sections regarding the risk of serious infections and the associated disease-causing organisms. ^[108]

Smoking cessation

A lifestyle change that may benefit patients with Crohn disease is smoking cessation. Tobacco use has been linked to increases in the number and severity of flares of Crohn disease, and smoking cessation alone is occasionally sufficient to achieve remission of refractory Crohn disease.

The top-down approach (ie, earlier use of immunomodulators and biologics) includes the need for steroid-enhanced mucosal healing and achieves an earlier and more complete remission than step-up therapy. A general rule of thumb is that once remission is achieved, the medications used to achieve remission should be continued, except steroids, which should be tapered off, because they have no role in maintaining remission ^[109] and their use may lead to debilitating illness, particularly after long-term use. Home infusion of IV hyperalimentation is becoming increasingly available for those rare patients with Crohn disease in whom prolonged bowel rest is necessary (eg, cases of severe fistulizing disease). Patients with a short bowel may require prolonged hyperalimentation.

Diseases of the lung (primarily chronic obstructive pulmonary disease [COPD]) in Crohn disease are common comorbidities, primarily because of smoking; however, cardiovascular disease, although common in the older patient, does not have any direct link with IBD. IBD may also be a factor in the treatment of prostate cancer (to avoid rectal injury), but is generally not a factor in breast cancer.

Most of the concerns regarding the interaction of other disease processes and IBD revolve around the medications used to treat various conditions; therefore, the physician treating the older patient must continually be aware of the potential for medication interactions. Although the advent of electronic medical records makes it easier to check for such interactions, it remains up to the physician to determine which interactions are clinically significant.

Aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs) are frequently used for cardiovascular and rheumatologic disorders; these agents and cyclooxygenase type 2 (COX-2) inhibitors are known to cause flares in IBD (not universally, but often enough to be clinically important). ^[110]

Most aminosalicylates do not have substantial interactions with non-IBD agents. The side effects of corticosteroids may be exacerbated in the older population, particularly in those with diabetes, accelerated bone loss, and cataract formation. The anti-TNF agents are generally contraindicated in patients with congestive heart failure (CHF) but can be used once the CHF is controlled. The immune-modifying agents have a clinically important interaction with allopurinol, as allopurinol tremendously increases the serum levels of mercaptopurine and azathioprine to the point where these agents can quickly manifest toxicity.

Ulcerative colitis is a surgically curable disease. However, Crohn disease can involve any segment of the gastrointestinal tract from the mouth to the anus; surgical resection is not curative, as recurrence is the norm. In addition, repeated need for surgery and bowel resection may result in short gut syndrome and dependence on parenteral nutrition.

Ulcerative colitis

Consider surgical intervention for patients in whom medical therapy fails, as it is curative for colonic disease, and for those with colonic dysplasia or malignancy. ^[3] Approximately 25%-30% of patients may require operative management. ^[1] The indications for colectomy are the following:

• Intractable inflammation

• Precancerous changes (high-grade dysplasia or proven multicentric, low-grade dysplasia confirmed by 2 expert pathologists)

• Intolerance to medical therapy

• Toxic megacolon

• Perforation

The surgical options for ulcerative colitis vary. Currently, the two  most common choices are proctocolectomy with ileostomy and total proctocolectomy with ileal pouch/anal anastomosis (IPAA).

The most common operation performed to treat ulcerative colitis is ileal pouch/anal anastomosis (IPAA). In this multistage procedure, a diverting ileostomy is performed and an ileal pouch is created and anastomosed directly to the anus, with complete removal of the rectal mucosa. After the ileoanal anastomosis is healed, the ileostomy is taken down, and flow through the anus is reestablished.

The major complication of this procedure is postoperative development of acute or chronic pouchitis. Very rarely, particularly in those with a preoperative diagnosis of indeterminate colitis, Crohn disease of the pouch may develop. IPAA offers an excellent option for younger patients with ulcerative colitis and those with concerns with body image. However, IPAA is also associated with a substantial rate of infertility (due to pelvic dissection).

Elective surgery can sometimes be performed laparoscopically. For fulminant colitis, the surgical procedure of choice consists of a subtotal colectomy with end ileostomy and creation of a Hartmann pouch.

A population-based study by de Silva et al showed that the primary predictors of severe postoperative complications are age and multiple comorbidities. Furthermore, the worst outcomes occurred when surgery was performed 14 or more days after hospital admission under emergency conditions in patients who had no response to medical treatment. ^[111]

For patients who plan to become pregnant, a subtotal colectomy is preferred to avoid the 48% decrease in fecundity with the IPAA procedure.

Crohn disease

Surgery for Crohn disease is most commonly performed in patients with complications of the disease (ie, strictures, fistulas). Approximately 70% of patients with ileocolonic Crohn disease require surgical intervention. ^[1]  In general, conservative resection is advocated (including potential stricturoplasty, as opposed to resective surgery) to preserve bowel length in case additional surgery is needed in the future. ^[4]

Although surgery is an important treatment option for Crohn disease, patients should be aware that it is not curative and that disease recurrence after surgery is the rule. Disease recurrence generally mimics the original disease pattern at the surgical anastomosis. Endoscopic evidence of recurrent inflammation is present in 93% of patients 1 year after surgery.

In segmental resection, a segment of intestine with active Crohn disease or a stricture is resected, and the remaining bowel is reanastomosed. In general, as little bowel as possible is resected, because the risk of disease recurrence is significant. ^[112]

In patients with a very short cicatrix stricture, a bowel-sparing stricturoplasty can be performed. In this procedure, a longitudinal incision is made across the stricture, and then the incision is repaired with a horizontal suture. All mucosa is spared, and the obstruction is relieved. As many as 6-8 stricturoplasties can be performed in a single operative session.

Stricturoplasty is associated with a 6%-8% rate of septic complications (2%-3% of patients require reoperation); this may be prevented with optimal preoperative management to control the inflammatory component of the stricture before surgical intervention.

Ileorectal or ileocolonic anastomosis is an option available to some patients who have distal ileal or proximal colonic disease. In patients with severe perianal fistulas, a diverting ileostomy or colostomy is an option. In this procedure, the distal colon is defunctionalized and a temporary ileostomy or colostomy is created. The ileostomy or colostomy is then taken down after 6 months or longer. Many patients who pursue this option choose to forego reanastomosis after placement of a stoma and a consequent improvement in quality of life. Approximately 50% of patients who have the reanastomosis performed have recurrences of perianal disease.

Symptomatic enteroenteric fistulas are generally resected, although recurrence is common. Postoperative medical therapy often prevents recurrence, although data are lacking regarding efficacy. A meta-analysis of nine randomized trials suggested that 5-ASA preparations provide a very modest benefit for maintenance. ^[87] The preferred program of prevention varies between immunomodulators and biologic therapy.

Contraception in the perioperative setting

Before undergoing major elective surgery, women with IBD should stop using combined oral contraception for a minimum of 4 weeks before the surgery, and alternative methods of contraception should be used. ^[113] Advise each patient when oral contraception can be restarted.

If a woman with IBD is considering sterilization, counsel her and her partner regarding alternative contraceptive methods (eg, long-acting reversible contraception, vasectomy). Note that in women with a history of pelvic or abdominal surgery, laparoscopic sterilization may not be considered an appropriate contraceptive method. ^[113]

Tapering corticosteroids in the postoperative setting

If possible, the use of corticosteroids should be minimized before surgery. Poor postoperative outcomes have been associated with prednisone doses greater than 30 mg/day. ^[1]

The World Gastroenterology Organization (WGO) recommendations for tapering corticosteroids depend on the duration of corticosteroid use, as follows ^[1] :

• Less than 1 month: abrupt cessation postoperatively is allowed

• 1-3 months, with a dose of 20 mg/day or greater: taper by 5 mg/day per week after surgery

• 3-6 months: taper by 2.5 mg/day per week

• More than 6 months: taper slowly, at 1 mg/wk or less once the dose is 10 mg/day

No known dietary or lifestyle changes prevent inflammatory bowel disease (IBD), and no known dietary substances have been consistently shown to cause activation of IBD. Tobacco use has been linked to increases in the number and severity of flares of Crohn disease, and smoking cessation can help achieve remission in patients with Crohn disease. Lactose intolerance is common in persons with Crohn disease or ulcerative colitis and can mimic symptoms of IBD.

Diet

Although diet has been well demonstrated to have little or no influence on inflammatory activity in persons with ulcerative colitis, it may influence symptoms. For this reason, patients are often advised to make a variety of dietary modifications, especially adaptation of a low-residue diet, although the evidence does not support a low-residue diet as beneficial in the treatment of ulcerative colitis. Such a diet, however, might decrease the frequency of bowel movements.

Unlike in patients with ulcerative colitis, diet can influence inflammatory activity in persons with Crohn disease. Nothing by mouth (NPO) can hasten the reduction of inflammation, as may the use of a liquid or predigested formula for enteral feeding. Although a meta-analysis in 1995 demonstrated that steroids were superior to liquid diet alone for Crohn disease, a liquid diet seemed superior to a regular diet for reducing inflammation. The problem with using enteral liquid diets, especially the predigested formulations, is that palatability limits the intake of adequate energy (calories) to meet patient requirements. Parenteral alimentation may be needed.

In a prospective study of 56 patients with quiescent Crohn disease on maintenance infliximab therapy (5 mg/kg, q 8 wk), Yamamoto et al found that concomitant enteral nutrition did not significantly improve the maintenance rate of clinical remission in patients with Crohn disease. ^[114] In the study, 32 patients received concomitant enteral nutrition (elemental diet infusion at night; a low-fat diet during the day), and 24 patients did not receive enteral nutrition and had no dietary restrictions. ^[114]

Multivitamin supplementation is recommended in patients with IBD. ^[1] For patients with vitamins B12 or vitamin D deficiency, supplementation of these vitamins should be given. The results of 2 studies suggest that the link between vitamin D and IBD may be of particular importance. ^{[115, 116, 117]}

In one of the studies, 3217 patients with Crohn disease or ulcerative colitis and low vitamin D levels had an increased risk of surgery and hospitalization. ^[116] Crohn disease patients with 25-hydroxyvitamin D levels lower than 20 ng/ml had an increased risk of surgery and IBD-related hospitalization than those with levels higher than 30 ng/ml. Similar estimates were seen for ulcerative colitis. In the other study, Crohn disease patients who took 2000 IU of vitamin D daily for 3 months gained muscle strength and improved quality of life. ^[117]

Patients receiving steroid therapy should receive vitamin D and calcium supplementation. Parenteral iron (IM weekly or IV) may be used in patients with chronic iron-deficiency anemia who are unable to tolerate the oral formulation. ^[1]

Activity

Generally, patients do not need to limit activity when IBD is quiescent. During disease flares, physical activity is limited only by the extent of fatigue and the abdominal pain or diarrhea the patient is experiencing. When abdominal pain persists beyond medical therapy­-induced resolution of the active inflammation, other causes of pain must be considered, including abscess, stricture, nephrolithiasis, IBS, and psychiatric disease.

In most instances, diarrhea limits activity primarily because of the lack of immediate access to toilet facilities in many locations and/or occupations. Dehydration may be an issue, often requiring IV hydration or the use of oral rehydration solutions.

Moderate to vigorous physical activity for as long as 12 weeks has been shown to improve symptom scores and many specific quality-of-life dimensions, including energy, sleep, emotion, and physical functioning. ^[118] This degree of activity was defined as 20-60 minutes of intense exercise 3-5 days per week. The improvements occur despite lack of change in body weight, oral-anal transit time, bowel movements per week, or stool consistency. This study also highlights that symptomatic deterioration is more likely in physically inactive individuals.

Clinicians are advised to review the prescribing information for medications in women who are attempting to conceive, are pregnant, or are breastfeeding. ^[113] All of the aminosalicylates (sulfasalazine, mesalamine, olsalazine, balsalazide) and corticosteroids appear to be safe in women in all phases of fertility, pregnancy, and lactation. Men should avoid sulfasalazine during periods when they and their mates are attempting to become pregnant.

Reproduction

In women with IBD, fertility is normal or only minimally impaired. The majority of case reports and small series show no adverse outcomes of pregnancies in patients with IBD who are taking immune modifiers. Birth defects have not been reported at a rate higher than that of the general population. If a patient is taking an immune modifier and becomes pregnant, current data support the consensus that continuing the immune modifier throughout the pregnancy is the safest course of action for both the mother and the fetus. ^[119]

The only agent that is contraindicated in women considering pregnancy is methotrexate (MTX), which has demonstrated teratogenic effects. MTX should be discontinued 3 months prior to planned conception.

For men with IBD, sulfasalazine can decrease sperm counts and sperm motility, causing a functional azoospermia; the other aminosalicylates do not have this effect. The sperm effects are reversible by discontinuing the sulfasalazine. No firm evidence indicates that the use of immune modifiers in the father leads to increased birth defects, although this has been suggested in one Spanish study.

Pregnancy

Most infants born to parents with IBD are healthy. The prevalence of prematurity, stillbirth, and birth defects is similar to that in the general population. The prevalence of spontaneous abortion is slightly higher in patients with IBD (12.2%) than in the general population (9.9%). Previous proctocolectomy or ileostomy is not an impediment to successful pregnancy; however, controversy exists regarding the type of delivery (cesarean or vaginal) that is most appropriate when a woman has had ileal pouch/anal anastomosis surgery. ^[113] Women who have undergone such a procedure should consult with their obstetricians and gastroenterologists. ^[113]

The aminosalicylates, including sulfasalazine, are safe during pregnancy. Folate supplements should be taken. Corticosteroids are also safe, but if high doses are needed near the end of the pregnancy, monitor the infant for signs of adrenal suppression. Continuation of immune modifiers (ie, 6-MP, azathioprine) appears to be safe in pregnancy, ^{[110, 120]} as well as metronidazole (Flagyl) and ciprofloxacin (Cipro).

It is considered safe to continue TNF-alpha inhibitors during pregnancy (FDA category B), but concerns have been raised about high levels of maternally administered anti-TNF agents being found in the fetal circulation. ^{[121, 122, 123, 124]} There is no documentation of any fetal harm with the use of any of the anti-TNF agents during pregnancy. Certolizumab does not cross the placenta. ^{[121, 122, 123, 124]}

In a retrospective, multicenter study, treatment of IBD with thiopurines and anti-TNF-alpha drugs did not increase the risk of complications during pregnancy or neonatal complications. ^[125] The rate of unfavorable Global Pregnancy Outcome and the rate of neonatal complications were lower in pregnant women treated with thiopurines alone than in those exposed to anti-TNF-alpha drugs or those not exposed to either group of agents.

Effective contraception must be used with certain drug therapy. ^[113] Both male and female partners receiving methotrexate should use effective contraception for a minimum of 3 months following treatment with this agent.

Other concerns that have been raised include the potential reduction of fertility with total abdominal colectomy with ileal pouch/anal anastomosis (IPAA) surgery (primarily because of adhesions). ^{[126, 127]} This possibility can likely be reduced by using a laparoscopic approach. ^[128]

According to the Faculty of Sexual and Reproductive Healthcare Clinical Effectiveness Unit in the United Kingdom, women with IBD should plan for conception when their disease is stable and well controlled. ^[113] Male and female patients require prepregnancy counseling to help them with the best management of their condition before conception occurs. ^[113]

Contraception precautions

Advise women who have Crohn disease with small bowel disease and malabsorption that oral contraception may have reduced effectiveness. ^[113] Additional contraception is recommended for women on combined hormonal contraception who are also receiving antibiotic regimens for less than 3 weeks, as well as for 7 weeks following cessation of the antibiotic. Note that certain medications prescribed for rectal or genital use may adversely affect the efficacy of condoms. ^[113] In addition, consider whether contraceptive agents may have an effect on diseases associated with IBD (eg, osteoporosis, venous thromboembolism, primary sclerosing cholangitis).

In women with IBD who will undergo major elective surgery, combined oral contraception should be discontinued for a minimum of 4 weeks before the procedure. ^[113] These women should use alternative contraception.

Breastfeeding

Sulfasalazine metabolites can be detected in the breast milk. Low concentrations of mesalamine and higher concentrations of its metabolites can also be detected in breast milk, but the significance of this is unknown. In addition, corticosteroids can also be detected in breast milk.

Immune modifiers are excreted in breast milk and should be considered only on a case-by-case basis; either the immune modifier should be discontinued or the infant should be bottle fed.

Antibiotics (metronidazole [Flagyl], ciprofloxacin [Cipro]) should generally be avoided during lactation, because they are excreted in breast milk; either breastfeeding or the drugs should be discontinued. These agents are probably safe for fertility and during pregnancy.

Anti-TNF agents (ie, infliximab, adalimumab) traverse the placenta, whereas certolizumab does not, because of the absence of the Fc fragment. They are found in the cord blood but not in breast milk.

Although small amounts of the topical agents are absorbed and thus may be excreted in breast milk, the concentrations are much lower than those with the oral forms of the same medications. These medications are probably reasonably safe in breastfeeding.

In patients with severe inflammatory bowel disease (IBD), with complications such as strictures or fistulas, and with flares requiring hospitalization, consultation with a surgeon is often required. Early consultation with a surgeon is particularly important in patients with severe disease or extraluminal complications, because delayed surgery can be associated with poorer outcomes.

An interventional radiologist may be consulted when percutaneous drainage of an abscess is desired. Specialty consultation is best for managing extracolonic manifestations (ie, uveitis, arthritis, dermatitis, sclerosing cholangitis). Also consider arranging consultations for patients with a registered dietitian and a stoma nurse, if indicated.