5-Aminosalicylates

5-ASA drugs, such as mesalamine and sulfasalazine, are no longer recommended for the treatment of CD. Sulfasalazine alone has shown moderate benefit in treating active disease, but it has not been shown to be effective in maintaining remission. Nevertheless, many physicians prescribe ASA drugs for mild CD because of their low toxicity, low cost, and familiarity. In particular, mesalamine (Pentasa), a controlled-release formulation of 5-ASA, is a favorite drug for CD involving the small bowel and colon because it releases approximately 50% of 5-ASA in the small intestine and the remaining 50% in the colon. Mesalamine suppositories and enemas are also used for distal left-sided disease. 5-ASA agents have a relatively safe toxicity profile. Kidney function may be checked annually because of a low risk of renal insufficiency. Interstitial nephritis is considered an idiosyncratic reaction and is not dose dependent. Rarely, a hypersensitivity reaction can occur, causing worsening abdominal pain, diarrhea, or hematochezia, which should prompt discontinuation of the drug. Although many physicians and patients still elect to use 5-ASA, it has not been proved that these agents affect the course of CD.

Antibiotics

No strong evidence exists to support the use of antibiotics in persons with active CD. However, antibiotics may be beneficial in treating suppurative disease, perianal complications, or hospitalized patients who have signs of infection. A common practice is to prescribe a 2-week course of ciprofloxacin, 500 mg by mouth twice a day, and metronidazole, 500 mg by mouth twice a day.

Corticosteroids

Corticosteroids are highly potent antiinflammatory medications used to achieve clinical remission in patients with active CD. They should not be used as long-term therapy because of their adverse effects. Short-term adverse effects include mood disturbances, fluid retention, hypertension, and weight gain. Long-term consequences include thinning of skin, poor wound healing, cataracts, diabetes, osteoporosis, adrenal insufficiency, and increased risk of infections. Corticosteroids can be administered parenterally, orally, or topically. Severely ill, hospitalized patients with CD benefit from intravenous corticosteroids, such as hydrocortisone, 300 mg per day, or methylprednisolone, 40 to 60 mg per day. Prednisone is the most commonly used oral corticosteroid, starting at 40 to 60 mg per day, and tapering by 5 to 10 mg every 5 to 7 days once remission is achieved. Enteric-coated budesonide, an analog of conventional corticosteroids, is an excellent and effective alternative for ileal and right-sided colonic CD. Because of its high first-pass metabolism in the liver, only 10% to 15% of budesonide is systemically bioavailable, thus conferring less toxicity than conventional steroids. Studies have shown that budesonide is effective in inducing remission or delaying relapse for up to 9 months, but evidence for its use in maintaining remission is lacking. The optimal dose to induce remission is 9 mg per day, followed by a 3 mg taper every 4 weeks. Physicians and patients should develop a management plan that aims to maintain steroid-free remission on a long-term basis, which typically includes the use of an immunomodulator or a biologic agent.

Immunomodulators

Thiopurines (e.g., azathioprine and 6-mercaptopurine [6-MP]) are the most common immunomodulators in the treatment of moderate to severe CD disease and are primarily used for the maintenance of remission. Because of their slow onset of action (up to several weeks), immunomodulators are not effective in inducing remission. Therefore, in patients with active disease, immunomodulators with a more rapid onset of action such as corticosteroids are typically prescribed. The standard dose of azathioprine is 2 to 2.5 mg/kg/day, whereas the dose of 6-MP is 1 to 1.5 mg/kg/day. Azathioprine is a prodrug that is converted to 6-MP, which is then metabolized into an active metabolite, 6-thioguanine nucleotide (6-TGN). Excess production of the 6-TGN metabolite can cause myelotoxicity and increased risk of infection. Excess production of the 6-methylmercaptopurine (6-MMP) metabolite can lead to hepatotoxicity. Therefore, before starting therapy, thiopurine methyltransferase (TPMT) enzymatic activity should be checked to assess potential risk for drug sensitivity and toxicity. Thiopurine is not recommended for patients with a low or undetectable TPMT level. In patients with low to intermediate TPMT activity, the dosage should be reduced, usually by 50%.

No standard method exists for monitoring blood tests. We recommend weekly complete blood cell count and liver function tests for the first month, then every other week for 1 month, then every 3 months. If the white blood cell count is less than 3000 per mm ³ or if transaminases are greater than three times the upper limits of normal, the dosage should be reduced or the drug should be discontinued. One key drug interaction is allopurinol, an inhibitor of xanthine oxidase, which interferes with the metabolism of azathioprine and 6-MP. This drug-drug interaction can elevate plasma levels of 6-TGN, which can suppress bone marrow function. Therapeutic drug monitoring for 6-TGN and 6-MMP are now commercially available. These tests are particularly useful in patients who did not respond to thiopurine treatment despite an adequate duration and dose of immunomodulator therapy. 6-TGN levels of greater than 235 pmol/8 × 10 ⁸ red blood cells correlate with a higher likelihood of response, whereas 6-MMP levels of greater than 5700 pmol/8 × 10 ⁸ red blood cells correlate with a higher likelihood of hepatoxicity.

Before initiating immunosuppressive therapy, patients are screened for latent tuberculosis and chronic hepatitis B. Age-appropriate vaccinations may be considered prior to initiating immunomodulators, especially live vaccines, given the risk of reactivation or dissemination in an immunocompromised host. There is also an increased risk of nonmelanoma skin cancers and a four- to fivefold increased risk of non-Hodgkin lymphoma. Therefore, annual skin surveillance is often recommended along with routine blood work.

Methotrexate, another immunomodulator, is often used in conjunction with a biologic agent to reduce antibody formation. Although less commonly used as monotherapy for CD, a reasonable amount of placebo-controlled data shows that methotrexate is effective for the induction and maintenance of remission. The dose is 25 mg once weekly administered subcutaneously, which is then lowered to 15 mg after 8 to 12 weeks if the patient improves. Because methotrexate is a folate antagonist, it is usually taken with folic acid, at a dose of 1 mg daily. The risk of infection and malignancy is slightly increased. Complete blood cell count and liver function tests are checked regularly. Methotrexate is classified as a category X drug in pregnancy because it has been associated with miscarriage and birth defects. Patients are counseled to use contraception while undergoing therapy and are advised to discontinue the drug for 6 months before planning for conception.

Biologic Agents

The introduction of biologic agents has substantially improved the care of patients with CD by effectively inducing and maintaining remission and reducing the need for hospitalization and surgery. Monoclonal anti–tumor necrosis factor (anti-TNF) antibodies are designed to bind to human TNF-α, thereby impairing binding to TNF-α receptor sites and resulting in downregulation of the cytokine-driven inflammatory response. Multiple studies have shown that anti-TNF agents are effective in inducing and maintaining remission in persons with moderate to severe CD. Additionally, anti-TNF therapy is the treatment of choice for perianal fistulas. Currently, three anti-TNF medications have been approved for the treatment of CD in the United States: infliximab, adalimumab, and certolizumab pegol. Infliximab and adalimumab are approved for the induction and maintenance of remission, but certolizumab has a higher failure rate in inducing remission. Infliximab is administered via intravenous infusion, whereas adalimumab and certolizumab are injected subcutaneously. These agents differ by their chemical structure but share similar adverse effects. The most common include infusion reaction or injection site reactions, which can be addressed easily. Most serious adverse effects include an increased risk of infection and non-Hodgkin lymphoma, especially with exposure to thiopurines concurrently or in the past. Anti-TNF monotherapy does not appear to be associated with an increased risk of lymphoma, but it is associated with melanoma. Latent tuberculosis, active hepatitis B, or fungal infections should be ruled out before starting biologic agents. Age-appropriate vaccinations and live vaccines may be initiated prior to starting biologic agents because of the potential risk of reactivation. Patients may be monitored with routine blood work every 3 to 6 months and with annual skin examinations. Commercially available tests to detect therapeutic levels and the presence of antibody toward infliximab and adalimumab can be helpful in persons with a poor response to anti-TNF therapy to determine the optimal dosage, interval of administration, or need to consider an alternative biologic agent.

Another therapeutic option is natalizumab, a humanized monoclonal antibody directed against cell adhesion molecule α ₄ β ₁ and α ₄ β ₇ integrins, which prevents T-lymphocyte adhesion to vascular cell adhesion molecule–1 and mucosal addressin–cell adhesion molecule–1 (MAdCAM-1), thus downregulating inflammation. Natalizumab was first shown to be effective in the treatment of multiple sclerosis but has since been shown to be effective in inducing and maintaining remission of moderate to severe CD. Use of this drug has been limited by the risk of progressive multifocal leukoencephalopathy (PML), and thus the U.S. Food and Drug Administration has restricted it to patients who have not responded to anti-TNF drugs. Before treatment with natalizumab is initiated, patients must be tested for the JC virus antibody to assess their risk of the development of PML.

Vedolizumab, a humanized monoclonal immunoglobulin G ₁ antibody, specifically binds to integrin α ₄ β ₇ but does not inhibit α ₄ β ₁ or α _E β _7. The agent inhibits adhesion of a gut-specific subset of T lymphocytes to MAdCAM-1 but not to vascular cell adhesion molecule–1. Because MAdCAM-1 resides almost exclusively in the gastrointestinal tract, vedolizumab does not affect systemic immune response or affect T-cell migration to the central nervous system and therefore may be the first gut-specific CD treatment. It does not appear to be associated with risk of PML, which is a significant advantage compared with natalizumab. The pivotal GEMINI 2 study demonstrated the efficacy and safety of vedolizumab in treating CD, which led to approval by the U.S. Food and Drug Administration in 2014. Many new agents, including ustekinumab and etrolizumab, are in development, and ongoing research continues to expand our repertoire of therapies for CD.

Combination Therapy

The Study of Biologic and Immunomodulator Naïve Patients in Crohn’s disease (SONIC), a single randomized controlled trial, demonstrated that combination therapy of immunomodulators and anti-TNF was superior to monotherapy in persons with moderate to severe CD. In this trial, combination therapy of azathioprine and infliximab was more effective than infliximab monotherapy, which, in turn, was more effective than azathioprine alone at maintaining clinical and endoscopic remission at 26 and 54 weeks. It is not clear whether azathioprine compounds antiinflammatory effects, but it does appear to enhance the response to infliximab by decreasing anti-infliximab antibodies and increasing infliximab levels. Combination therapy was not associated with a higher risk of serious infections during the trial, and evidence in subsequent studies was insufficient to conclude whether combination therapy increases the risk of opportunistic infections or malignancies. Furthermore, the risks and benefits beyond 1 year are not known. Expert opinion states that results from SONIC can be extrapolated to adalimumab. Controversy exists about duration of combination therapy and whether combination therapy provides benefit for persons who have failed to respond to immunomodulator therapy. Some patients might elect monotherapy because of a higher value of avoiding any potential risk of serious complications or malignancies compared with an increased chance of inducing and maintaining remission.