INFLAMMATORY BOWEL DISEASE: CROHN’S DISEASE AND ULCERATIVE COLITIS

INFLAMMATORY BOWEL DISEASE: CROHN’S DISEASE AND ULCERATIVE COLITIS

  1. 1
    Current Diagnosis

    • The most common clinical symptom of ulcerative colitis (UC) is bloody diarrhea, which is often associated with cramping abdominal pain.

    • Clinical manifestations of Crohn’s disease (CD) are highly variable, but the most common constellation is right lower quadrant abdominal pain and nonbloody diarrhea, often accompanied by weight loss and other constitutional symptoms.

    • The hallmarks of CD are transmural inflammation, fistula formation, small-bowel fibrosis, and patchy inflammation; these may affect any segment of the gastrointestinal tract (with terminal ileal involvement in two thirds of patients). In contrast, inflammation in UC is limited to mucosa and submucosa and is diffuse, with the rectum most commonly involved. Inflammation extends proximally to varying degrees among patients.

    • There is no single diagnostic test for inflammatory bowel disease; instead, the diagnosis is made based on several corroborative features.

    •   Potential infectious causes of symptoms should be ruled out.

    • Endoscopic examination is valuable in establishing the extent of inflammation, obtaining mucosal biopsy specimens, and excluding certain infectious agents.

    • Serology studies, such as anti–Saccharomyces cerevisiae antibodies (ASCA), perinuclear antineutrophilic cytoplasmic antibody (pANCA), anti-porin antibody (OmpC), and anti-flagellin antibody (CBir1), are occasionally useful to predict disease behavior.

    • Lactoferrin and Calprotectin, which are inflammatory markers found in stool, can be used to assess for postoperative recurrence in patients with Crohn’s disease. A few studies have demonstrated the utility of elevated inflammatory markers in predicting future clinical flares.

    • Computed tomographic enterography can help distinguish inflammatory component from fibrosis.

    • Rectal magnetic resonance imaging, endoscopic ultrasound, or examination under anesthesia can be used to fully delineate perianal fistulizing disease.

    • In centers with available expertise, limited right lower quadrant ultrasound with doppler can be used for evaluation of ileal Crohn’s disease.

  2. 2
    Current Therapy

    • Mesalamine products in adequate dosage and appropriate formulation can be effective therapy for mild to moderately active ulcerative colitis (UC) and in maintaining remission.

    • Mesalamine products may be effective in mild Crohn’s disease (CD), and the formulation selected should be determined by disease location.

    • Steroids are useful in patients with moderate to severe CD or UC, but their use should be limited as much as possible because of frequent side effects and complications.

    • Immunomodulators such as Azathioprine (Imuran)1 and 6- mercaptopurine (Purinethol)1 may be used as an adjunct therapy to minimize steroid use in patients who are steroid dependent and to minimize formation of neutralizing antibodies in patients receiving antibody-based biologic agents.

    • Anti–tumor necrosis factor (anti-TNF) biologic agents such as infliximab (Remicade) and adalimumab (Humira) are effective in patients with moderate to severe inflammatory CD or UC that is unresponsive to conventional treatments. Golimumab (Simponi), which is another anti-TNF agent, recently has been approved for induction and maintenance of remission in ulcerative colitis. It has been demonstrated to result in improvement of endoscopic appearance of colonic mucosa. Certolizumab pegol (Cimzia) may be used to maintain response. Immunomodulators and biologic agents may be used independently or in combination for treatment of inflammatory bowel disease and for maintaining surgically induced remission in CD.

    • Risks of opportunistic infections, hematologic and cutaneous malignancies, and neurologic complications, in addition to other adverse effects of biologic therapy with or without immunomodulators, should be discussed with the patient.

    • The proven role of antibiotics is limited to septic complications, perianal disease, small intestinal bacterial overgrowth, and pouchitis.

    • Nataluzimab (Tysabri), an anti-α4  agent, is effective in some patients with refractory CD, including those for whom anti-TNF therapy has failed.

    • Another Integrin inhibitor, Vedolizumab (Entyvio) has been recently approved by FDA for induction andmaintenance of remission and response in both Crohn’s disease and ulcerative colitis.

    1 Not FDA approved for this indication.

  3. 3
    Clinical Manifestations

    The cardinal symptom of ulcerative colitis (UC) is bloody diarrhea. Symptoms of tenesmus and the sensation of incomplete evacuation may dominate in patients who have disease limited to the rectum. Although cramping abdominal pain is often present, it is a more prominent symptom in patients with Crohn’s disease (CD).

    Physical examination of patients with UC may detect left lower quadrant and left upper quadrant tenderness, and occasionally the extent of colonic involvement may be deduced by careful physical examination. Rebound tenderness, distention, or guarding suggests the development of the dreaded complication of toxic megacolon, which may supervene in patients with severe UC.

    Patients with CD have more widely varying symptoms as a result of the highly variable sites of involvement and the range of phenotypic forms. Disease manifestations may be dominated by inflammatory activity per se, by fistula formation (fistulizing or perforating disease), or by stricture formation (stricturing disease). Perianal fistulas can be a distressing manifestation and may parallel clinical flares. The symptom complex of right lower quadrant pain, nonbloody diarrhea, and weight loss is most common because of the frequent involvement of the ileum. However, in CD with colonic involvement (with or without more proximal disease), symptoms may be indistinguishable from those of UC. Intestinal narrowing may be caused by edema due to inflammation, fibrosis from chronic inflammation, or a combination of these factors. The presence of a mass in the right lower quadrant suggests inflammatory ileal disease (and probably abscess formation), whereas right lower quadrant pain in conjunction with obstructive symptoms in the absence of a mass may be suggestive of stricture formation. Fistula disease can manifest with especially variable symptoms because of the many anatomic structures that can be involved (e.g., fecaluria and pneumaturia in those with fistulas to the bladder). Rectovaginal fistulas may lead to passage of air from the vagina. Patients with upper gastrointestinal CD may present with dysphagia, early satiety, and fear of food leading to weight loss.

    Diarrhea is common but not universal in CD. Inflammation of the ileum or of the colon can cause diarrhea. Occasionally, diarrhea is caused by small intestinal bacterial overgrowth, especially in patients with fistulizing disease, or it may be induced by bile salts in those with ileal disease (or after ileal resection).

  4. 4
    Diagnosis

    Diagnosis of inflammatory bowel disease (IBD) is based on the combination of clinical features, laboratory abnormalities, imaging studies (e.g., upper gastrointestinal series with small bowel follow- through and abdominal computed tomography or magnetic resonance imaging or both), and endoscopic findings including examination of mucosal biopsies. None of these tests alone is diagnostic of IBD. In a patient with new symptoms and in those patients with flares if appropriate, infectious agents should be ruled out. Common pathogens that can mimic IBD are Salmonella, Shigella, Aeromonas, Campylobacter, Yersinia, Clostridium difficile, Plesiomonas, and parasites such as Giardia lamblia and Entamoeba; these should be ruled out. In an immunocompromised host (including patients with established IBD receiving immunosuppressive therapy), viral infections such as cytomegalovirus and herpes simplex virus may cause ulcers suggestive of IBD. Endoscopic imaging is often very useful. The constellation of findings in endoscopy and other studies, together with the histologic and clinical features, usually allows a reliable distinction between UC and CD. However, in as many as 10% of patients, it may not be possible to make the distinction with confidence, and such patients are said to have indeterminate colitis. The distinguishing features of UC and CD are presented in Table 1.

    Table 1

    Distinguishing Features: Crohn’s Disease and Ulcerative Colitis

    Features                   Crohn’s Disease                                                                                        Ulcerative Colitis
    Location Any part of gastrointestinal tract Colonic
    Inflammation Transmural Mucosal/submucosal
    Smoking Smokers higher than expected Appears to be protective
    Risk of colorectal cancer Elevated in colonic Crohn’s Elevated
    Risk of intestinal cancer Elevated in small-bowel Crohn’s disease NA
    hsCRP Elevation common Elevation not common
    Serology ASCA, OmpC, CBir1 pANCA
    Surgery Recurrence common Total proctocolectomy may be curative
    Fistulas Common Very rare
    FDA-approved biologic agents Infliximab (Remicade), adalimumab (Humira), certolizumab pegol (Cimzia), natalizumab (Tysabri), vedolizumab (Entyvio) Infliximab, adalimumab, golimumab, vedolizumab (Entyvio)
    Immunomodulator therapy Azathioprine (AZA, Imuran),1 6-mercaptopurine (6MP, Purinethol),1 methotrexate  (MTX, Trexall)1 AZA, 6MP, cyclosporine (Sandimmune, Neoral)1
    Endoscopic features Skip lesions Contiguous involvement
    Strictures Common Colorectal cancer unless proven otherwise
    Genetic markers* NOD2, ATG16L1, IRGM, IL23R, IL12B, STAT3, NKX2-3 IL12B, STAT3. NKX2-3

    Abbreviations: ASCA = anti–Saccharomyces cerevisiae antibodies; CBir1 = anti-flagellin antibody; FDA = U.S. Food and Drug Administration; hsCRP = high-sensitivity C-reactive protein; NA = not applicable; OmpC = anti-porin antibody; pANCA = perinuclear antineutrophilic cytoplasmic antibody.

    1  Not FDA approved for this indication.

    • Not approved for diagnosis. More than 50 genes have been associated with susceptibility to IBD.

    Hematologic abnormalities include evidence of microcytic anemia, elevated white blood cell count in peripheral blood, and thrombocytosis. Markers of inflammation such as erythrocyte sedimentation rate (ESR) and high-sensitivity C-reactive protein (hsCRP) may also be elevated, the latter more commonly in CD than in UC. Very high hsCRP may be associated with infections such as cytomegalovirus or Clostridium difficile.

    Serologic measurements of perinuclear antineutrophilic cytoplasmic antibody (pANCA), anti–Saccharomyces cerevisiae antibodies (ASCA— immunoglobulin G and immunoglobulin A), anti-porin antibody (OmpC), and anti-flagellin antibody (CBir1) are occasionally helpful as corroborative evidence and to help identify patients who are at higher risk for complicating events. They may also be useful in differentiating between CD and UC in patients for whom colectomy is being considered when diagnostic ambiguity remains.

    Hypoalbuminemia can be a sign of poor nutritional status, and these patients should be considered for total parenteral nutrition, particularly if surgery is being planned.

    Among the imaging modalities commonly used in diagnosis and management of IBD, computed tomography of the abdomen and pelvis can alert physicians to perforation, bowel obstruction, and extent of inflammation. Computed tomographic enterography can be used to evaluate the degree and extent of inflammation in the small bowel (Figure 1). In cases of stenotic lesions of the small bowel, it can be especially helpful in identifying the inflammatory component, as evidenced by mural stranding. Lack of mural stranding in stenotic portions of small bowel suggests fibrosis, and if there is evidence of proximal dilation in a symptomatic patient, resection or strictureplasty should be considered. Ultrasound of the right lower quadrant can be an effective imaging modality in select patient populations to assess for postoperative recurrence, disease activity, and response to therapy.

    FIGURE 1 Computed tomographic enterography. Mural stratification; ileal wall thickening (arrow) suggestive of active inflammation; dilated loops of small bowel (double arrow) consistent with partial obstruction; and diffuse increased density of the subcutaneous and intraperitoneal fat compatible with anasarca are seen in this image. (Courtesy Dr.  Cecelia Brewington, MD.)

    Magnetic resonance imaging can be a helpful adjunct, along with examination under anesthesia and rectal endoscopic ultrasonography, in cases of perianal fistulizing disease.

    Endoscopic examination is helpful to establish the extent of disease and obtain tissue for histologic examination. Esophagogastroduodenoscopy should be done if upper gastrointestinal CD is suspected. Single-balloon and double-balloon enteroscopy have allowed gastroenterologists to obtain tissue samples from jejunum and proximal ileum. Capsule endoscopy can be a useful alternative, although it does not allow tissue sampling and should not be used if even limited obstruction is suspected. Colonoscopy is helpful in diagnosis and during follow-up to assess response to various therapeutic modalities. It can also be used to obtain biopsy specimens from the colon and terminal ileum to be examined for findings of IBD or potentially confounding processes, including some infections. Stool Calprotectin can be a valuable tool to assess efficacy of therapies, monitor for postsurgical recurrence in patients with Crohn’s disease, and differentiate between inflammatory and noninflammatory etiologies of diarrhea in patients with IBD.

  5. 5
    Treatment

    Once the diagnosis is confirmed, the treatment of IBD is based on manifestation, location, patient history, and severity of symptoms.

    Treatment algorithms for IBD are usually divided into management of mild, moderate, and severe disease. The roles of various agents have evolved, and as more data are being accumulated, patients are treated earlier with agents that had been reserved for more severe disease in the past. Treatment goals for these patients are:

    • Improving quality of life to as close to normal as possible
    • Maintaining remission
    • Avoiding surgery
    • Minimizing the risk of steroid dependence
    • Minimizing the risk of treatment-associated complications

    Ulcerative Colitis

    In the initial evaluation of UC patients, it is important to establish the extent and degree of inflammation and the concomitant presence of extraintestinal manifestations. Extent and severity of UC are judged on clinical symptoms, basic laboratory parameters (complete blood count and albumin level), and colonoscopic findings. Disease limited to the rectum and distal colon may be treated with local mesalamine therapy, in a suppository (Canasa), foam (Salofalk),2 or enema (Rowasa) formulation. Newly diagnosed patients with mild to moderate disease activity should be given an appropriate oral formulation of mesalamine (Asacol). Mesalamine formulation as Asacol has been discontinued in the United States. Patients who are on Asacol can be switched to alternate mesalamine formulations, keeping in mind that the replacement agent should deliver an equivalent amount of mesalamine to the colon. One of the substitute mesalamine preparations is Delzicol, which delivers 400 mg of mesalamine per capsule. Antidiarrheal agents may provide symptomatic relief once infectious causes of colitis have been excluded. Colonic release budesonide (Uceris) recently has been approved for short-term (up to 16 weeks) therapy of mild to moderate ulcerative colitis.

    If remission is achieved with a mesalamine formulation, the same dose of mesalamine is continued for maintenance of remission. For an occasional flareup suggested by symptoms of recurrence and documented by sigmoidoscopy or colonoscopy, steroids may be used. For patients who have frequent flareups (more than two per year), initiation of therapy with a conventional immunomodulator or biologic agent (infliximab, adalimumab, or golimumab) should be considered. Colonic release budesonide formulation utilizing MMX technology, marketed as Uceris, has been shown to be an effective but probably short-term (up to 16 weeks) therapy for active mild to moderate ulcerative colitis.

    For patients with moderate disease unresponsiveness to mesalamine or severe disease, a topical, oral, or intravenous corticosteroid (depending on extent and severity) may be necessary, but it should be used for as short a period as possible, and, if it is not possible to taper and discontinue the steroid within 6 weeks, an immunomodulator should be added.

    Surgical intervention should be considered for patients who have not responded to therapy with biologic agents, steroids, and/or cyclosporine (Neoral).1 Patients who have high-grade dysplasia or colorectal cancer are also candidates for surgery.

    Crohn’s Disease

    Optimal treatment of CD is based on many factors, including location, severity, specific clinical manifestation and complications, prior clinical course intervention, whether fistulas are present, potential fibrostenotic strictures, history of steroid dependence, history of failure with other agents, and contraindications (e.g., malignancy, opportunistic infections, tuberculosis, intolerance to medications).

    Before deciding on treatment options, it is important to delineate behavior (fistulizing, stricturing, or inflammatory), location (ileal, colonic, or ileocolonic), and severity and to assess for the presence of extraintestinal complications and nutritional deficiencies.

    In patients with mildly active, localized ileocecal disease, treatment has historically begun with a suitable mesalamine product (although the effectiveness of this approach remains uncertain).1 More recently, oral budesonide (Entocort EC, a steroid targeted to the ileum that undergoes extensive first-pass metabolism to minimize systemic steroid effects) has been used. For those with more extensive or severe disease, conventional systemic steroids (prednisone) may be used, but if it is not possible to wean the patient off steroids within 6 weeks, an immunodulatory agent should be started, typically 6-mercatopurine (Purinethol)1/azathioprine (Imuran)1 or, in those unable to tolerate these agents, low-dose methotrexate (Trexall).1 For patients with moderate to severe disease, treatment should include an anti-tumor necrosis factor (anti-TNF) agent with or without immunomodulator therapy. Natalizumab (Tysabri), an anti-α4 integrin, is an alternative and may be used if anti-TNF therapy fails.

    Before starting therapy with a biologic agent, patients should have a purified protein derivative (PPD) test and a hepatitis B surface antibody determination. Once biologic therapy begins, patients should continue to have an annual PPD test. QuantiFERON-TB Gold testing is a possible alternative to PPD for testing. This requires patients to come for testing once, as opposed to twice for PPD. We recommend checking for John Cunningham (JC) virus antibody before starting therapy with natalizumab. JC virus is a polyomavirus which is responsible for progressive multifocal leukoencephalopathy. Those testing positive should not be started on natalizumab. Patients who test negative should be tested for exposure at least twice a year.

    Plans for alternative therapies should be made for patients who have not responded to a biologic agent within 12 weeks.

    Perianal fistulizing disease, in the absence of abscess, can be treated with a combination of antibiotics, seton placement, immunomodulator therapy, and biologic agents. Complex perianal fistulizing disease may require a diverting ostomy.

  6. 6
    Therapeutic Options

    Mesalamine Preparations

    Aminosalicylate preparations have been used for the treatment of UC and CD. Some data suggest that mesalamine has limited efficacy in patients with CD.

    In patients with limited distal UC (e.g., proctitis), treatment may be begun with a mesalamine enema (Rowasa) or suppository (Canasa). For more extensive disease, oral therapy (Asacol) or an appropriate substitute mesalamine product should be used.

    Combination therapy (oral administration as well as enemas/suppositories) has been shown to be more effective in inducing remission than either modality alone. In general, the dosage that induces remission is used for maintenance of remission (Table 2).

    Table 2

    Mesalamine Products Indicated for Ulcerative Colitis

    Aminosalicylate Product                                                        Daily Dosage Frequency
    Azulfidine  (sulfasalazine tablet) 0.5 g–4 g qid
    Delzicol 2.4 g tid
    Pentasa  (mesalamine  controlled-release tablet) 2–4 g qid
    Colazal (balsalazide capsule) 6.75 g tid
    Dipentum  (olsalazine capsule) 1 g bid
    Lialda  (mesalamine  delayed-release tablet) 2.4–4.8 g qd
    Canasa (mesalamine rectal suppository)* 1 g qd
    Rowasa (mesalamine rectal enema) 4 g qd
    Apriso (mesalamine delayed and extended-release capsule) 1.5 g qd
    • Indicated for ulcerative proctitis.
    •   Indicated for distal ulcerative colitis.

    Steroids

    The National Co-operative Crohn’s Disease Study and the European Co-operative Crohn’s Disease Study demonstrated that steroids are efficacious in inducing remission but ineffective in maintaining remission. Among patients who have received steroids, about 26% will have a partial response, and 16% will have no response; among those who have had a complete or partial response, about 28% will become steroid dependent. The requirement for surgery is high in the latter group of patients; about 38% require surgery by the end of 1 year.

    The adverse effects of steroids are many and varied and can be classified as early effects and delayed effects associated with prolonged use (>12 weeks). Acne, moon facies, mood changes, sleep disturbances, gastrointestinal intolerance, hyperglycemia, hypertension, weight gain, and ulcers of the gastrointestinal tract can be seen early. Formation of cataracts, aseptic necrosis, suppression of the hypothalamic-pituitary axis, and myopathy are associated with prolonged use. Loss of bone density, previously thought to occur only with chronic use, may be evident in bone density studies after as little as 2 weeks of therapy.

    Budesonide (Entocort EC) is used for ileal inflammatory and right- sided colonic CD, with lower expected incidences of acne, moon facies, adrenal suppression, and loss of bone mineral density.

    Alternative therapies (immunomodulators, biologic agents) should be discussed with the patient if there has been no response to steroids in a few weeks.

    Immunomodulatory Therapy

    Azathioprine1 and 6-mercaptopurine1 are immunomodulators used as steroid-sparing agents for both CD and UC. Immunomodulators have been shown to modestly reduce the incidence of postsurgical recurrence in CD. The onset of action of these agents is slow, up to 3 to 4 months. Some toxicities are associated with genetic variants in the enzymes responsible for catabolism of azathioprine and 6- mercaptopurine, most notably thiopurine methyl transferase (TPMT). Most (89%) patients have wild-type TPMT (full TPMT enzyme activity), 11% have intermediate enzyme activity, and 0.3% have none. In patients with full TPMT enzyme activity, therapy should be started with 1.5 mg/kg/day of 6-mercaptopurine or 2.5 mg/kg/day of azathioprine; those with intermediate activity should have the dosage reduced by half. Those who do not have any TPMT expression should not be started on these agents because of the high risk of bone marrow toxicity.

    Some complications, including pancreatitis, hepatotoxicity, and serum sickness–like syndrome, cannot be predicted. It is recommended that patients starting these medications have a complete blood count and liver function tests performed every other week while their medications are being adjusted. Once they are on a stable dosage, these tests should be done every 2 to 3 months.

    Parenteral methotrexate1 15 to 25 mg/week can be used to induce remission in patients with CD that has not responded to conventional agents. Once remission has been achieved, oral methotrexate1 15 mg can be used to maintain remission. Methotrexate is absolutely contraindicated in pregnancy. Leukopenia, hepatic fibrosis, nausea and vomiting, and hypersensitivity reactions are potential side effects. Risk of hepatic fibrosis is associated with a cumulative dose of more than 1.5 g, diabetes, and concomitant use of alcohol.

    Cyclosporine

    In patients with severe UC, intravenous cyclosporine (Sandimmune)1 at a dose of 2 to 4 mg/kg/day has been shown to be effective in inducing remission. A significant proportion of these patients may still require colectomy within 1 year. Those patients who have achieved response and remission on intravenous cyclosporine should be started on oral cyclosporine (Neoral)1 for a few months, together with prophylaxis against Pneumocystis. 6-Mercaptopurine or azathioprine can also be used as maintenance agents.

    Side effects commonly seen with cyclosporine include renal dysfunction, seizures (particularly in patients with hypocholesterolemia), hypertension, gingival hyperplasia, electrolyte abnormalities, and hirsutism.

    Biologic Agents

    Infliximab is a chimeric (murine-human) monoclonal anti-TNF antibody that has been approved for induction and maintenance of remission in both CD and UC. It was initially approved for the treatment of fistulizing CD, and subsequent studies showed it to be effective in maintenance therapy as well. In several other studies, it was found to be efficacious in reducing steroid use, length of hospital stay, and surgical intervention and achieving mucosal healing.

    Infliximab is administered intravenously with or without premedication to avoid allergic reactions.

    For induction, infliximab 5 mg/kg is administered at weeks 0, 2, and 6, and maintenance is begun at 5 mg/kg every 8 weeks. Some patients require dose escalation because of diminution of response or failure to maintain remission. In these patients, depending on the clinical scenario, the dose should be increased to 10 mg/kg or the interval reduced to every 6 weeks. In the past, infliximab was routinely used with concomitant immunomodulator therapy to reduce the possibility of infliximab antibodies, but this practice has been associated with a higher risk for a rare hepatosplenic T-cell lymphoma (predominantly in the pediatric population), leading to reconsideration of the need for concomitant immunomodulators in some patients. However, results from the recently released Study of Biologic and Immunomodulator Naive Patients in Crohn’s Disease (SONIC) trial demonstrated the superiority of combination therapy over either immunomodulator or infliximab alone, especially in patients with elevated C-reactive protein and ulcers in their baseline colonoscopy. Because reactivation of latent tuberculosis has been reported, patients should undergo a PPD test or QuantiFERON-TB gold and chest radiography before beginning therapy. Available data, although limited, suggests that biologic agents (Infliximab, Adalimumab, Certolizumab and Tysabri) are safe for conception and pregnancy as well as breast feeding.

    Other Anti–Tumor Necrosis Factor Antibodies

    Adalimumab

    Recently, adalimumab (Humira), a recombinant fully human immunoglobulin targeting TNF, was approved for use in CD. In the CLASSIC and CHARM trials, adalimumab was demonstrated to be an effective agent in inducing and maintaining remission. It has also been shown to be effective in patients who have lost response to infliximab or are intolerant to it, but it has not yet been approved for treatment of UC. Serious reactions, reactivation of tuberculosis, allergic reactions, lupus-like reactions, and demyelinating diseases are some of the concerns.

    For induction, adalimumab 160 mg is given subcutaneously at week 0, 80 mg at week 2, and then, for maintenance of remission, 40 mg every other week.

    Certolizumab

    Certolizumab (Cimzia) is a polyethylene glycolated Fab fragment of humanized anti-TNF monoclonal antibody approved for use in CD. In the PRECISE 1 and 2 studies, certolizumab was shown to result in modest improvement in response but no clinically significant improvement in remission.

    Golimumab

    Golimumab (Simponi) is another monoclonal TNF antibody that has been approved for the treatment of moderate to severe ulcerative colitis. It should be considered as one of the treatment options when patients have begun failing therapy with mesalamine products or are at risk for developing steroid dependence. After two starter doses it is a monthly self-injectable treatment.

    Anti-α4 Therapy

    Natalizumab

    Natalizumab (Tysabri) is a humanized monoclonal antibody against the α4 integrin subunit, a molecule involved in cellular adhesion that is required for recruitment of key immune cells to sites affected by IBD. In several studies, it has been shown to be efficacious in inducing remission and maintaining response in CD patients. Enthusiasm has been tempered by the apparent risk for progressive multifocal leukoencephalopathy, a rare but fatal opportunistic infection. Before initiating therapy with this agent, patient will need to be enrolled in the TOUCH program (www.tysabri.com) and should be tested for evidence of prior exposure to JC virus. If the test is positive, alternative therapies should be considered. If the test is negative, JC virus antibody testing should be done at least twice a year while the patient is on natalizumab.

    Vedolizumab (Entyvio) is another humanized α4, β7 integrin inhibitor that mediates its anti-inflammatory activity in the gastrointestinal tract via MAdCAM pathway. It does not affect CSF T lymphocyte immunophenotype and it activity seems to be localized in the gut.

    The treatment regimens for UC and CD are summarized in Box 1.

    Box 1  
    Summary of Treatment Regimen

    Ulcerative Colitis

    Proctitis

    • Initial treatment choices
      • Mesalamine suppositories (Canasa) or enemas (Rowasa) to induce remission
      • Steroid foam enemas (Cortifoam) to induce remission
      • Mesalamine suppositories or enemas to maintain remission
    • Second-line treatment choices
      • Oral mesalamine in combination with local therapy
      • Adjunctive treatment with antibiotics: ciprofloxacin (Cipro),1 metronidazole (Flagyl),1 or rifaximin (Xifaxan)1
      • Probiotics

    Left-Sided Colitis

    • Initial treatment choices
    • Oral mesalamine product with or without local therapy
    • Second-line treatment choices
      • Oral or intravenous steroids budesonide (Uceris)
      • Immunomodulator therapy
      • Infliximab (IFX, Remicade), adalimumab (Humira), golimumab (Simponi)
      • Cyclosporine (Sandimmune)1 on an inpatient basis (avoid cyclosporine after IFX therapy due to risk of severe immunosuppression)

    Pancolitis

    • Initial treatment choices
      • Oral mesalamine with a short course of oral or intravenous steroids including colonic-release budesonide
    • Second-line treatment choices
      • Immunomodulator therapy
      • Infliximab, adalimumab, golimumab
      • Cyclosporine on an inpatient basis (avoid cyclosporine after IFX therapy due to risk of severe immunosuppression)

    Crohn’s Disease

    Ileocecal Inflammatory Crohn’s Disease

    • First-line treatment
      • Oral mesalamine (ileo-colonic release mesalamine product for ileal disease; Pentasa for more proximal small-bowel disease)1
      • Budesonide (Entocort EC) 9 mg PO qd
      • Immunomodulator therapy
      • Biologic agents with or without concomitant immunomodulators

    Ileal Stricturing Disease

    • No proximal dilation
      • Trial with budesonide or biologic agents (patients with elevated hsCRP are more likely to respond)
    • Proximal small-bowel dilation
      • Consider surgical approach

    Internally Fistulizing Disease without Intraabdominal Abscess

    • Stricture immediately distal to fistula
      • Surgical approach
    • No stricture
      • Biologic agents with or without concomitant immunomodulators

    Externally Fistulizing Disease without Intraabdominal Abscess

    • Biologic agents with or without concomitant immunomodulators

    Fistulizing Disease with Intraabdominal Abscess

    • Intravenous antibiotics as appropriate
    • Percutaneous drainage if appropriate
    • Surgical drainage if indicated
    • Biologic agents with or without concomitant immunomodulators once infectious process has been treated

    Perianal Crohn’s Disease without Abscess  Formation

    • Antibiotics: Ciprofloxacin (Cipro),1 metronidazole (Flagyl),1 rifaximin (Xifaxan)1
    • Immunomodulators
    • Biologic agents with or without concomitant immunomodulators
    • Seton placement
    • Diverting ostomy

    Colonic Crohn’s Disease

    • Oral steroids to induce remission
    • Immunomodulator therapy
    • Biologic agents with or without concomitant immunomodulator therapy

    Abbreviations: hsCRP = high-sensitivity C-reactive protein.

    1 Not FDA approved for this indication.

     

  7. 7
    References

    Booya F., Akram S., Fletcher J.G., et al. CT enterography and fistulizing Crohn’s disease: Clinical benefit and radiographic findings. Abdom Imaging. 2009;34(4):467–475.

    Feagan B.G., Panaccione R., Sandborn W.J., et al. Effects of adalimumab therapy on incidence of hospitalization and surgery in Crohn’s disease: Results from the CHARM study. Gastroenterology. 2008;135(5):1493–1499.

    Ghosh S., Goldin E., Gordon F.H., et al. Natalizumab for active Crohn’s disease. N Engl J Med. 2003;348(1):24–32.

    Hanauer S.B., Sandborn W.J., Kornbluth A. Delayed-release oral mesalamine at 4.8 g/day (800 mg tablet) for the treatment of moderately active ulcerative colitis: The ASCEND II trial. Am J Gastroenterol. 2005;100(11):2478–2485.

    Lichtenstein G.R., Yan S., Bala M. Infliximab maintenance treatment reduces hospitalizations, surgeries, and procedures in fistulizing Crohn’s disease. Gastroenterology.

    2005;128(4):862–869.

    Podolsky D.K. Inflammatory bowel disease. N Engl J Med.

    2002;347(6):417–429.

    Thomsen O.O., Cortot A., Jewell D., et al. A comparison of budesonide and mesalamine for active Crohn’s disease. International Budesonide-Mesalamine Study Group. N Engl J Med. 1998;339(6):370–374.

    Thukral C., Travassos W.J., Peppercorn M.A. The role of antibiotics in inflammatory bowel disease. Curr Treat Options Gastroenterol. 2005;8(3):223–228.

    Xavier R.J., Podolsky D.K. Unraveling the pathogenesis of inflammatory bowel disease. Nature. 2007;448(7152):427–434.

    2  Not availabel in the United  States.

    1  Not FDA approved for this  indication.

KNOWLEDGE BASE
About Genomic Medicine UK

Genomic Medicine UK is the home of comprehensive genomic testing in London. Our consultant medical doctors work tirelessly to provide the highest standards of medical laboratory testing for personalised medical treatments, genomic risk assessments for common diseases and genomic risk assessment for cancers at an affordable cost for everybody. We use state-of-the-art modern technologies of next-generation sequencing and DNA chip microarray to provide all of our patients and partner doctors with a reliable, evidence-based, thorough and valuable medical service.

X