Medication Summary
The goals of pharmacotherapy in patients with Crohn disease are to reduce morbidity, to prevent complications, and to maintain nutritional status.
Investigators reported the first use of a validated electrospray ionization LC-MS/MS method in human plasma for the simultaneous quantification of up to seven monoclonal antibodies (adalimumab, cetuximab, infliximab, rituximab, secukinumab, tocilizumab, and trastuzumab) acting against different pharmacologic targets. [152] This method has the potential to open up the field of therapeutic drug monitoring to many monoclonal antibodies, including for adalimumab, in patients with Crohn disease. [152]
Management of diarrhea
Chronic diarrhea in Crohn disease responds well to antidiarrheal agents such as loperamide (2-4 mg), diphenoxylate with atropine (1 tablet), and tincture of opium (8-15 drops). Such agents may be administered up to 4 times daily, but they should not be given to patients with active colitis, because of the risk of developing toxic megacolon.
Patients with terminal ileal disease may not absorb bile acids normally, which can lead to secretory diarrhea in the colon. These patients may benefit from bile acid sequestrants such as cholestyramine (2-4 g) and colestipol (5 g 2 or 3 times daily before meals).
Abdominal cramps may be reduced with propantheline (30 mg before meals and at bedtime), dicyclomine (10-20 mg), or hyoscyamine (0.125 mg). These drugs should not be used if there is the possibility of a bowel obstruction.
Management of bowel inflammation
For colon and small bowel inflammation, anti-inflammatory drugs or antibiotics are helpful. Neither sulfasalazine nor balsalazide alleviates small bowel disease. Products such as mesalamine, which releases 5-aminosalicylic acid (5-ASA) in the distal small bowel secondary to pH changes are more useful in patients with small intestinal Crohn disease.
According to a systematic review, antituberculosis therapy, macrolides, fluoroquinolones, 5-nitroimidazoles, and rifaximin (alone or in combination) have been shown to induce remission in active Crohn disease and ulcerative colitis. [153] Further trials of antibiotic therapy are necessary in order to determine the best course of single or combination antibiotic therapy.
Long-term maintenance with mesalamine (800 mg 3 times daily) may delay clinical relapse. Prednisone (40-60 mg/day) is generally helpful in acute inflammation. Oral glucocorticoid preparations such as budesonide are useful for patients with isolated terminal ileal inflammation and may reduce systemic side effects.
Steroids are not indicated for maintenance therapy, because of serious complications, such as aseptic necrosis of the hip, osteoporosis, cataract, diabetes, and hypertension. Accordingly, once remission is achieved, the agent is slowly tapered (5-10 mg every 1-2 weeks).
If steroid withdrawal proves difficult, immunosuppressants such as azathioprine (2 mg/kg/day) or its active metabolite, 6-mercaptopurine (6-MP), may be considered. Response is usually observed within 3-6 months. Mycophenolate mofetil 500 mg twice daily in 2 divided doses is well tolerated by patients and can be used to reduce the steroid dose. [2, 85]
Management of fistulae
Fistulae between bowel loops (eg, ileoileal, ileocecal, or ileosigmoid) are usually benign and may not produce any major problems. Medical management is used to treat underlying infections and symptoms with oral metronidazole (1 g/day) for at least 1-2 months.
Infliximab is effective in patients who have refractory perianal and enterocutaneous fistulae. Current clinical practice is to give it 5 mg/kg by intravenous (IV) infusion at 0 weeks, 2 weeks, and 6 weeks, followed by maintenance IV infusions every 8 weeks. On average, the effect lasts for 12 weeks.
5-Aminosalicylic Acid Derivatives
Class Summary
The 5-ASA derivative agents are used to treat mild-to-moderate Crohn disease and to maintain remission.
Mesalamine rectal (Canasa, Rowasa)
Rectal mesalamine is a formulation of mesalamine that specifically releases 5-ASA in the distal colon. This agent elicits an anti-inflammatory effect by an unknown mechanism.
Mesalamine (Asacol, Lialda, Apriso)
Products such as mesalamine, which releases 5-ASA in the distal small bowel secondary to pH changes, are more useful in patients with small intestinal Crohn disease. Long-term maintenance with mesalamine may delay clinical relapse. This agent is better tolerated than sulfasalazine and has fewer adverse effects.
Sulfasalazine (Azulfidine)
Sulfasalazine is useful mainly in colonic disease because the active compound, 5-ASA, is released in the large bowel by bacterial degradation of the parent compound. Sulfasalazine does not alleviate small bowel disease; it acts locally in the colon to reduce the inflammatory response and systemically inhibits prostaglandin synthesis. It has no additive or steroid-sparing effects when used in conjunction with corticosteroids. In contrast to its action in ulcerative colitis, sulfasalazine does not seem to maintain remission in Crohn disease.
Balsalazide (Colazal)
Balsalazide is an active component of sulfasalazine and is metabolized to mesalamine by intestinal flora. It has an anti-inflammatory effect, but its exact mechanism of action is not known. Balsalazide is used to treat ulcerative colitis.
Corticosteroids
Class Summary
Corticosteroids are used to treat active moderate to severe Crohn disease. They are not indicated for maintenance therapy. A short course of corticosteroid therapy is indicated in patients with severe systemic symptoms (eg, fever, nausea, and weight loss) and in those whose condition does not respond to anti-inflammatory agents.
Budesonide is available in an ileal controlled-release form and is used for the treatment of ileal or right-side colonic disease. Budesonide induces remission in active Crohn disease but is less effective than other standard glucocorticosteroids and is of no benefit in preventing relapse. [89]
Prednisone
Prednisone exerts anti-inflammatory effects through decreased capillary permeability, impaired neutrophil chemotaxis, release of anti-inflammatory cytokines, decrease of production of eicosanoids, and stabilization of lysosomal membranes. This agent is generally helpful in acute inflammation.
Methylprednisolone (Solu-Medrol, Medrol, Depo-Medrol)
Methylprednisolone exercises anti-inflammatory effects through decreased capillary permeability, impaired neutrophil chemotaxis, release of anti-inflammatory cytokines, decreased production of eicosanoids, and stabilization of the lysosomal membrane.
Budesonide (Entocort EC)
Budesonide alters levels of inflammation in tissues by inhibiting multiple types of inflammatory cells and decreasing the production of cytokines and other mediators involved in inflammatory reactions.
Hydrocortisone (Cortenema, Anusol-HC, Cortifoam)
Adrenocortical steroids act as potent inhibitors of inflammation. They may cause profound and varied metabolic effects, particularly in relation to salt, water, and glucose tolerance, in addition to their modification of the immune response of the body.
Prednisolone (Pediapred, Prelone, Orapred)
Prednisolone may decrease inflammation by reversing increased capillary permeability and suppressing polymorphonuclear leukocyte (PMN) activity. It is a commonly used oral agent. Prednisolone is used for an oral taper of steroids, which may reduce the emotional effects of steroid withdrawal and the risk of the development of adrenocortical insufficiency. However, these risks are not very high after only 3 days of treatment with high-dose steroids, and most neurologists do not use a prednisone taper.
Immunosuppressants
Class Summary
Immunosuppressant agents are used off label to treat moderate-to-severe Crohn disease, to treat steroid-dependent or steroid-refractory disease, and to maintain remission.
Mercaptopurine (Purinethol)
6-MP and its prodrug azathioprine are purine analogues; they interfere with protein synthesis and nucleic acid metabolism and have cytotoxic effect on lymphoid cells. If steroid withdrawal proves difficult, immunosuppressants such as 6-MP may be considered.
Azathioprine (Imuran, Azasan)
Azathioprine antagonizes purine metabolism and inhibits synthesis of DNA, RNA, and proteins. It may decrease proliferation of immune cells, which lowers autoimmune activity.
Methotrexate (Trexall, Rheumatrex)
Methotrexate is used for the treatment of moderate-to-severe Crohn disease and maintenance of remission. It is effective in inducing and maintaining remission in chronic Crohn disease in adults and has been shown to be effective and well tolerated for maintenance of remission in children. Methotrexate is a structural analogue of folic acid that inhibits binding of dihydrofolic acid to the enzyme dihydrofolate reductase. It impairs DNA synthesis, induces apoptosis, and reduces interleukin (IL)-1 production.
Tacrolimus (Prograf, Hecoria)
Tacrolimus is an immunomodulator produced by the bacteria Streptomyces tsukubaensis. Its mechanism of action is similar to that of cyclosporine. Tacrolimus may be effective in treating Crohn disease.
Monoclonal Antibodies
Class Summary
Monoclonal antibodies are used in the treatment of moderate-to-severe active Crohn disease or fistulizing disease that is unresponsive to other medical therapy.
Infliximab (Inflectra, Remicade)
Infliximab is a chimeric mouse-human monoclonal antibody against tumor necrosis factor (TNF)-α that shows promise in the treatment of Crohn disease. This agent blocks TNF-α in the serum and at the cell surface, leading to the lysis of TNF-producing macrophages and T cells. Infliximab has been approved for the treatment of pediatric Crohn disease.
Adalimumab (Amjevita, Cyltezo, Humira, Hadlima, Hyrimoz, Adalimumab-atto, Adalimumab-adbm, Adalimumab-bwwd, Adalimumab-adaz)
Adalimumab is indicated for the induction and remission of moderate-to-severe active inflammatory Crohn disease. This agent is a recombinant human immunoglobulin (Ig) G1 monoclonal antibody specific for human TNF. It binds specifically to TNF-α and blocks interaction with p55 and p75 cell-surface TNF receptors. This interferes with the cytokine driven inflammatory processes. Adalimumab also lyses surface TNF-expressing cells in vitro in the presence of complement, but it does not bind to TNF-β (lymphotoxin). The FDA approved adalimumab-atto, adalimumab-adbm, adalimumab-adaz, adalimumab-bwwd as biosimilars and not as interchangeable drugs.
Certolizumab pegol (Cimzia)
Certolizumab pegol is indicated for moderate-to-severe Crohn disease in individuals whose condition has not responded to conventional therapies. It is a pegylated anti–TNF-α blocker, and its action results in disruption of the inflammatory process.
Ustekinumab (Stelara)
Ustekinumab inhibits interleukin (IL)-12 and IL-23 cytokines, which play a key role in inflammatory and immune responses. It is indicated for adults with moderately to severely active Crohn disease who have failed or were intolerant to immunomodulators or corticosteroids, but never failed treatment with a tumor necrosis factor (TNF) blocker. It is also indicated for those who failed or were intolerant to treatment with 1 or more TNF blockers.
Alpha 4 Integrin Inhibitors
Class Summary
Integrin inhibitors are emerging as options for moderate-to-severe active IBD in patients who have had an inadequate response with, lost response to, or were intolerant to a TNF blocker or immunomodulator; or had an inadequate response with, were intolerant to, or demonstrated dependence on corticosteroids.
Natalizumab (Tysabri)
Natalizumab is indicated for moderate-to-severe Crohn disease in patients who have had inadequate responses to other therapies. It is a monoclonal antibody that binds α4β7 and α4β1 that results in inhibition of leukocyte adhesion and migration to areas of inflammation.
Vedolizumab (Entyvio)
Vedolizumab is a recombinant humanized monoclonal antibody that binds specifically to α4β7 integrin. It blocks the interaction of α4β7 integrin with mucosal addressin cell adhesion molecule-1 (MAdCAM-1) and inhibits the migration of memory T-lymphocytes across the endothelium into inflamed gastrointestinal parenchymal tissue. It is indicated for both ulcerative colitis and Crohn disease.
Antibiotics
Class Summary
Antibiotics are used in the treatment of mild-to-moderate, fistulizing, and perianal disease. Antibiotics may change the microbial flora of the intestine and have a potential effect on the cell-mediated immune system.
Metronidazole (Flagyl)
Metronidazole is an imidazole ring–based antibiotic that is active against various anaerobic bacteria and protozoa. It is sometimes used in combination with other antimicrobial agents (except for Clostridium difficile enterocolitis). Metronidazole also possesses immunosuppressive and anti-inflammatory properties.
Ciprofloxacin (Cipro)
A fluoroquinolone, ciprofloxacin has activity against pseudomonads, streptococci, methicillin-resistant Staphylococcus aureus (MRSA), Staphylococcus epidermidis, and most gram-negative organisms, but it has no activity against anaerobes. Ciprofloxacin inhibits bacterial DNA synthesis and, consequently, growth.
Antidiarrheals
Class Summary
Chronic diarrhea in Crohn disease responds well to antidiarrheal agents such as loperamide (2-4 mg), diphenoxylate with atropine (1 tablet), and tincture of opium (8-15 drops). Such agents may be administered up to 4 times daily, but they should not be given to patients with active colitis, because of the risk of developing toxic megacolon.
Loperamide (Imodium, Diamode)
Loperamide, which is available over the counter, acts on intestinal muscles to inhibit peristalsis and to slow intestinal motility. It prolongs the movement of electrolytes and fluid through the bowel and increases the viscosity and loss of fluids and electrolytes. Loperamide improves stool frequency and consistency, reduces abdominal pain and fecal urgency, and may exacerbate constipation.
Diphenoxylate-atropine (Lomotil)
The combination of diphenoxylate with atropine consists of 2.5 mg of diphenoxylate, which is a constipating meperidine congener, and 0.025 mg of atropine to discourage abuse. The preparation inhibits excessive gastrointestinal (GI) propulsion and motility, but it may exacerbate constipation.
Bile Acid Sequestrants
Class Summary
Patients with terminal ileal disease may not absorb bile acids normally, which can lead to secretory diarrhea in the colon. These patients may benefit from bile acid sequestrants such as cholestyramine and colestipol.
Cholestyramine (Prevalite, Questran, Questran Light)
Cholestyramine is used for diarrhea associated with Crohn disease. It binds bile acids, thereby reducing damage to the intestinal mucosa. Cholestyramine also reduces the induction of colonic fluid secretion. It forms a nonabsorbable complex with bile acids in the intestine, thereby, in turn, inhibiting enterohepatic reuptake of intestinal bile salts.
Colestipol (Colestid)
Colestipol forms a soluble complex after binding to bile acid, increasing fecal loss of bile acid–bound low-density lipoprotein cholesterol.
Anticholinergic Agents
Class Summary
Abdominal cramps may be reduced with anticholinergic agents such as propantheline, dicyclomine, or hyoscyamine. These drugs should not be used if there is the possibility of a bowel obstruction.
Dicyclomine (Bentyl)
Dicyclomine treats GI motility disturbances. It blocks the action of acetylcholine at parasympathetic sites in secretory glands, smooth muscle, and the central nervous system (CNS). Adverse effects are dose-dependent.
Hyoscyamine (Levsin, Levbid, Anaspaz, Symax, NuLev)
Hyoscyamine blocks the action of acetylcholine at parasympathetic sites in smooth muscle, secretory glands, and the CNS, thereby exerting antispasmodic effects. This agent decreases fecal urgency and pain.
Propantheline
Propantheline is a quaternary ammonium antimuscarinic agent with peripheral effects that are similar to those of atropine. It inhibits GI motility and decreases gastric acid secretion.
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Crohn disease. The colonoscopy image reveals a large ulcer and inflammation of the descending colon in a 12-year-old boy with Crohn disease.
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Crohn disease. This laparoscopic view depicts creeping fat along the mesentery of the terminal ileum.
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Crohn disease. On this laparoscopic photograph, the mesentery of the terminal ileum is being coagulated with a sealing device (LigaSure). Note that the ligation of the mesentery proceeds near the border of the ileum rather than at the base of the mesentery.
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Crohn disease. This postoperative photograph depicts incisions used for laparoscopic ileocolectomy in a 14-year-old male adolescent with obstruction of the terminal ileum. Note the 2-cm incision in the right lower abdomen, through which the specimen was extracted and extracorporeal anastomosis performed. A 12-mm umbilical incision is nicely hidden in the depths of the umbilicus. A 5-mm incision is visible in the left lower abdomen, and another is in the left suprapubic region just above the top of the pants.
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Crohn disease. Colonic granuloma in a patient with Crohn disease is shown (hematoxylin-eosin staining). Image courtesy of Dr E. Ruchelli.
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Crohn disease. Aphthous ulcers. A double-contrast barium enema examination in a patient with Crohn colitis demonstrates numerous aphthous ulcers.
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Crohn disease. This double-contrast barium enema study demonstrates marked ulceration, inflammatory changes, and narrowing of the right colon in a patient with Crohn colitis.
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Crohn disease. Cobblestoning in Crohn disease. This is a spot view of the terminal ileum from a small bowel follow-through study. It demonstrates linear longitudinal and transverse ulcerations that create a cobblestone appearance. Also, note the relatively greater involvement of the mesenteric side of the terminal ileum and the displacement of the involved loop away from the normal small bowel secondary to mesenteric inflammation and fibrofatty proliferation.
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Crohn disease. Crohn disease of terminal ileum. The small bowel follow-through study demonstrates the string sign in the terminal ileum. Also, note the pseudodiverticula of the antimesenteric wall of the terminal ileum, secondary to greater distensibility of this less-involved wall segment.
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Crohn disease. This spot view of the terminal ileum from a small bowel follow-through study in a patient with Crohn disease demonstrates the string sign, consistent with narrowing and stricturing. Also, note a sinus tract originating from the medial wall of the terminal ileum and the involvement of the medial wall of the cecum.
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Crohn disease. Enterocolic fistula in a patient with Crohn disease. The double-contrast barium enema study demonstrates multiple fistulous tracts between the terminal ileum and the right colon adjacent to the ileocecal valve (so-called double-tracking of the ileocecal valve).
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Crohn disease. Active small bowel inflammation in a patient with Crohn disease. This computed tomography scan demonstrates small bowel wall thickening, mesenteric inflammatory stranding, and mesenteric adenopathy.
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Crohn disease. This computed tomography scan from a patient with terminal ileal Crohn disease shows an enteroenteral fistula (arrow) between loops of diseased small intestine.
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Crohn disease. A teenaged patient with Crohn disease underwent contrast-enhanced, upper gastrointestinal computed tomography scanning with small-bowel follow-through. Several loops of small bowel are in the pelvis. Note the loop of distal bowel with thickened wall (solid arrow), which is contrasted with a less-involved loop of bowel in which the intestinal wall is not thickened at all (dotted arrow).
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Crohn disease. This computed tomography scan depicts Crohn disease in the fundus of the stomach.
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Crohn disease. This magnetic resonance image demonstrates an inflamed terminal ileum in 10-year-old girl with Crohn disease.
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Crohn disease. The histologic image shows granuloma in the mucosa of a patient with Crohn disease.
Tables
Characteristic |
||
|
Crohn Disease |
Ulcerative Colitis |
Distribution |
Entire gastrointestinal tract |
Colon only, though gastritis is recognized |
Skip lesions |
Continuous involvement proximally from rectum |
|
Pathology |
Full thickness |
Mucosa only |
Granulomas (15-30% in biopsy specimens; 40-60% in surgically resected bowel) |
No granulomas |
|
Radiology |
Entire gastrointestinal tract |
Colon only |
Skip lesions |
Continuous involvement proximally from rectum |
|
Fistulae, abscesses, fibrotic strictures |
Mucosal disease only |
|
Cancer risk |
Increased |
Estimated to be 3% at 10 years, 8% at 30 years, and 18% at 30 years after diagnosis [47] ; risk is higher in patients with primary sclerosing cholangitis and long-standing colitis (> 8-10 y); may be lower in subsequent studies (see Intestinal Manifestations). |
Presentation |
||
|
Crohn Disease |
Ulcerative Colitis |
Bleeding |
Occasional |
Very common |
Obstruction |
Common |
Uncommon |
Fistulae |
Common |
None |
Weight loss |
Common |
Uncommon |
Perianal disease |
Common |
Rare |
Operative Indication |
Factors for Considering Surgery |
Failed medical therapy |
|
Perforation |
|
|
|
For target or “innocent bystander” organs, diseased bowel is typically resected, noninflamed bowel primarily closed, and other internal organs primarily closed or allowed to heal by secondary intention Note: Operative intervention may be avoided for asymptomatic internal fistulae |
|
Obstruction |
|
|
|
Inflammation |
|
|
|
Hemorrhage |
Mesenteric angiography with embolization may be attempted when adequate endoscopic visualization is not possible or when the bleeding source cannot be identified; if this technique is not successful or the patient is hemodynamically unstable, laparotomy with or without intraoperative endoscopy and resection of the responsible bowel segment may be required |
Neoplasia |
|
|
|
|
|
Growth retardation and EIMs |
|
|
|
ASCRS = American Society of Colon and Rectal Surgeons; DALM = dysplasia-associated lesion or mass; EIM = extraintestinal manifestation; GI = gastrointestinal. Source: Strong SA, Koltun WA, Hyman NH, Buie WD, for the Standards Practice Task Force of The American Society of Colon and Rectal Surgeons. Practice parameters for the surgical management of Crohn’s disease. Dis Colon Rectum. 2007;50(11):1735-46. [7] |
|
Site |
Surgical Intervention |
Terminal ileum, ileocolon, upper GI tract |
|
|
|
|
|
Note: Surgical services should be available in case of perforation |
|
Colon |
|
|
|
|
|
ASCRS = American Society of Colon and Rectal Surgeons; GI = gastrointestinal. Source: Strong SA, Koltun WA, Hyman NH, Buie WD, for the Standards Practice Task Force of The American Society of Colon and Rectal Surgeons. Practice parameters for the surgical management of Crohn’s disease. Dis Colon Rectum. 2007;50(11):1735-46. [7] |
|
