Generic
Brand
Daily dose
Site of action
Sulfasalazine
Azulfidine
4–6 g daily in divided doses
Colon
Azulfidine EN-Tabs
4–6 g daily in divided doses
Colon
Mesalamine
Canasa (suppositories)
500–1,000 mg daily QHS
Rectum
Rowasa (enemas)
1–4 g daily QHS
Rectum/distal colon
Asacol
2.4–4.8 g daily in divided doses
Terminal ileum/colon
Pentasa
2–4 g daily in divided doses
Distal small bowel/colon
Lialda
2.4–4.8 g daily in a single dose
Colon
Apriso
1.5 g daily in a single dose QAM
Colon
Olsalazine
Dipentum
1.5–3 g daily
Colon
Balsalazide
Colazal
6.75 g daily
Colon
Topically delivered preparations of 5-ASA (suppositories, enemas) have not been evaluated in controlled trials in patients with distal colonic CD.
SSZ and 5-ASA are not recommended for maintenance of remission.
Headache and gastrointestinal upset are common dose-dependent side effects of SSZ.
SSZ depletes folate and should therefore be given with a folate supplement.
SSZ may cause reversible sperm abnormalities, leading to relative infertility that reverses within 3 months of stopping the drug.
Antibiotics
Antibiotics are valuable in treating perianal or perforating complications of CD.
Side effects occur in up to 50 % of patients who take metronidazole short term and include gastrointestinal intolerance, metallic taste, and reaction to alcohol.
Peripheral neuropathy, possibly irreversible, may occur with long-term use.
Ciprofloxacin was shown in one study to be as effective as 5-ASA for achieving remission in mild-to-moderate active disease.
Combination treatment with metronidazole and ciprofloxacin may be an alternative to steroid treatment in mild-to-moderate active CD.
Side effects include gastrointestinal upset, skin reactions, and an increase in transaminase levels.
Ciprofloxacin has been associated with rare cases of tendonitis and Achilles tendon rupture.
Budesonide
Multiple randomized controlled trials have demonstrated the efficacy of budesonide over placebo for the induction of remission in patients with mild-to-moderately active ileal or ileo-right colonic disease.
Budesonide has also been shown to be a more effective treatment than 5-ASA.
Several studies have compared budesonide with prednisone and found that rates of clinical remission were similar in each group and the occurrence of corticosteroid-related side effects was considerably less.
Moderate-to-Severe Crohn’s Disease
The treatment options for these patients include corticosteroids, biologic agents, and the early addition of immunomodulator therapy with azathioprine (AZA), 6-mercaptopurine (6-MP), or methotrexate (MTX) as an adjunct or a bridge to maintenance therapy.
Oral Corticosteroids
Oral corticosteroids are effective for the induction of remission in patients with moderate-to-severe CD.
Prednisone doses of 40–60 mg daily are often prescribed for 2–6 weeks to induce remission.
50–70 % of patients will achieve remission at these doses. Higher doses of prednisone (1 mg/kg) or methylprednisolone (1 mg/kg) have had somewhat higher response rates of 80–90 %; however, there is an increased incidence of side effects.
Prednisone doses are tapered by 5–10 mg/week until 20 mg and then by 2.5–5 mg weekly from 15 or 20 mg until discontinuation of therapy.
Corticosteroids are not recommended as maintenance agents.
50 % of patients treated for active symptoms with a corticosteroid will become “steroid dependent” or “steroid resistant.”
Studies suggest that younger patients, smokers, and/or those with colonic disease have the highest risk of becoming corticosteroid dependent.
Common findings include insomnia, fluid retention, acne, moon face, abdominal striae, weight gain, hypertension, hyperglycemia, glaucoma, cataracts, and mood disturbances. Musculoskeletal complications, such as osteoporosis, osteonecrosis, and myopathy, are important side effects.
Immunomodulators
AZA and 6-MP are effective for maintaining a corticosteroid-induced remission and are beneficial as steroid-sparing agents.
In clinical practice, AZA 2.0–2.5 mg/kg and 6-MP 1.01.5 mg/kg are used for maintenance therapy.
Clinical benefit may not be evident for 3–4 months after initiation but may be durable.
Adverse events include leukopenia, liver function abnormalities, pancreatitis (3–7 %), and lymphoma.
Monitoring of complete blood counts, initially every 1–2 weeks, then, at least every 3 months, is recommended.
Nonmelanoma skin cancers and cervical cancer may also occur more frequently. There is a slightly increased risk of lymphoma.
Genetic polymorphisms of thiopurine methyltransferase (TPMT), the primary enzyme metabolizing 6-MP, have been identified, and drug metabolite levels may be measured.
Prior to starting AZA or 6-MP, TPMT enzyme activity or genotype should be determined.
AZA and 6-MP should be avoided in patients deficient in TPMT.
Patients with heterozygous genotype of intermediate activity should initiate therapy at reduced doses, generally, AZA 1.0–1.25 mg/kg or 6-MP 0.5–0.75 mg/kg daily.
Methotrexate (MTX)
MTX may be used to induce remission and as a steroid-sparing agent in patients with corticosteroid-refractory or corticosteroid-dependent CD.
Folic acid 1 mg daily is routinely given.
MTX is an alternative agent to AZA and 6-MP for maintenance of remission.
MTX is contraindicated in pregnancy as it is teratogenic and abortifacient.
Biologic Therapy
Biologic therapies (primarily anti-tumor necrosis factor antibodies) have been considered when CD is moderately to severely active despite therapy with aminosalicylates, corticosteroids, and/or immunomodulators or if corticosteroids or immunomodulators are contraindicated, not tolerated, or ineffective.
Biologic therapy may also be indicated if patients are corticosteroid dependent or refractory.
Patients with complications such as draining fistulas or extraintestinal manifestations may derive particular benefit from biologic therapy.
Infliximab (chimeric monoclonal antibody) has been shown to effectively induce remission in patients with moderate-to-severe CD and to maintain remission in those patients.
Infliximab is also useful for treating patients with corticosteroid-dependent and fistulizing disease.
Patients treated with infliximab experience fewer hospitalizations and surgeries related to CD.
The occurrence of extraintestinal manifestations, such as spondyloarthropathy, arthralgias, and pyoderma gangrenosum, may be reduced with infliximab.
Approximately 30 % of patients have no response to infliximab, and not all responders have a complete response.
Elevated C-reactive protein (CRP), nonstricturing and pure colonic disease subtypes, and concomitant use of immunomodulators have been described as positive predictors for response to infliximab. AZA and 6-MP are most commonly used as concomitant suppression. Methotrexate (MTX) may also be used.
Initial response rates to adalimumab and certolizumab pegol were 58 % (the Netherlands randomized patients).
Initiation of more intensive treatment early in the course of disease may result in better outcomes.
Significantly more patients treated with infliximab alone or the combination of infliximab and azathioprine had relief of symptoms than patients treated with azathioprine alone.
Patients with CD who are naive to immunomodulators and biologic agents are more likely to have enhanced mucosal healing when they are treated with infliximab and AZA and attain a corticosteroid-free clinical remission.
Response to anti-TNF agents decreases with longer duration of disease.
Natalizumab is a humanized monoclonal antibody that targets human α4 integrin, thereby interfering with trafficking of leukocytes into the mucosa.
Natalizumab is indicated for the induction and maintenance of response or remission in patients with moderate to severely active CD.
Natalizumab should only be used in patients who are refractory or intolerant to immunomodulators and anti-TNF therapy and for whom surgery is not an acceptable option. See Table 28.2 for specific indications and Table 28.3 for dosing guidelines for biologic therapies.
Table 28.2
Indications for biologic therapies
Indication
Crohn’s disease
Ulcerative colitis
Infliximab
Adalimumab
Certolizumab
Natalizumab
Infliximab
Induction of response and remission
X
X
X
X1
X
Maintenance of response and remission
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