Ulcerative Colitis Treatment & Management

Updated: Jun 22, 2018
  • Author: Marc D Basson, MD, PhD, MBA, FACS; Chief Editor: BS Anand, MD  more...
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Treatment

Approach Considerations

The treatment of ulcerative colitis (UC) is made on the basis of the disease stage (active, remission), extent (proctitis, distal colitis, left-sided colitis, pancolitis), and severity (mild, moderate, severe). [10] In general, it relies on initial medical management with corticosteroids and anti-inflammatory agents, such as sulfasalazine, in conjunction with symptomatic treatment with antidiarrheal agents and rehydration. [55] Surgery is contemplated when medical treatment fails or when a surgical emergency (eg, perforation of the colon) occurs. Surgical options include total colectomy (panproctocolectomy) and ileostomy, total colectomy, and ileoanal pouch reconstruction or ileorectal anastomosis. In an emergency situation, subtotal colectomy with end-ileostomy is recommended. [5, 6, 7]

Chronic ulcerative colitis is associated with an increase in the risk of carcinoma, and colonic carcinoma may easily be missed in the setting of ulcerative colitis. Patients with ulcerative colitis must be made aware of the significant risk of colon cancer, and surgical intervention in nonacute cases should be encouraged after 10 years of disease or when symptoms are refractory or steroid dependent. Indications for surgery in ulcerative colitis vary and are discussed in detail under Indications for Surgery.

As yet, no evidence suggests that regular endoscopic screening of patients with ulcerative colitis improves survival. However, the current standard of practice by many gastroenterologists is to continue screening these patients at regular intervals, owing to the risk of cancer development and possible legal implications if malignancy is not detected. Mucosal healing should be determined endoscopically or using fecal calprotectin levels approximately 3 to 6 months after treatment initiation. [44]

Consultations

Consultations include a gastroenterologist, as well as a surgeon for severe or fulminant colitis.

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Treatment of Mild Disease

In mild ulcerative colitis (UC) disease confined to the rectum, topical mesalazine (Asacol) given by suppository is the preferred therapy. Enemas and foams are less effective because their concentration in the rectum rapidly diminishes. Left-sided colonic disease is best treated with a combination of mesalazine suppository and an oral aminosalicylate. Combined oral and topical therapy is better than either route alone. Of the oral aminosalicylates, sulfasalazine has the longest history. Sulfasalazine is 5-aminosalicylate (5-ASA) coupled to a sulfapyridine. It is poorly absorbed in the proximal bowel, and the bacteria in the colon uncouple the 5-ASA from the sulfa moiety, allowing 5-ASA to exert its anti-inflammatory effect on the colonic mucosa by inhibiting prostaglandin synthesis.

Mesalazine, another 5-ASA-containing molecule, is better tolerated orally than sulfasalazine and has become the preferred medication. A meta-analysis previously suggested that doses of at least 2 g per day are more effective in inducing remission and preventing relapse, but that exceeding 2.5 g per day might not have any additional benefit. [56] However, more recent studies have shown that higher doses are beneficial in patients not responding to lower doses (eg, 2.4 g vs 4.8 g). [57, 58, 59]

After remission, long-term maintenance therapy is encouraged, but compliance rates are low. One systematic review analyzed the outcomes of once-daily dosing of mesalazine compared to a conventional dosing schedule (minimum of twice daily). It was concluded that once-daily dosing is as effective as divided dosing for relapse prevention, and such daily dosing may increase compliance, although this has not been formally evaluated. [60, 61]

Systemic steroids are indicated when the disease fails to quickly respond to aminosalicylates.

In January 2013, the US Food and Drug Administration (FDA) approved an extended-release oral formulation of budesonide for the treatment of active mild-to-moderate ulcerative colitis in adults patients. [62] Because budesonide is a potent corticosteroid that exerts only minimal systemic activity, this formulation provides the benefit of a powerful anti-inflammatory drug delivered locally while avoiding many of the systemic side effects associated with systemic steroids.

A pooled analysis of the efficacy and safety outcomes from two phase 3 studies of oral budesonide MMX (Multi Matrix colonic delivery) 9 mg and 6 mg and placebo in 672 patients with mild-to-moderate ulcerative colitis found that budesonide MMX 9 mg was safe, efficacious, and well tolerated for inducing remission in these patients.  [63] The budesonide MMX 9 mg resulted in significantly greater combined clinical and colonoscopic remission rates compared with placebo, whereas the budesonide MMX 6 mg did not. Symptom resolution and colonoscopic improvement rates were also significantly greater with budesonide MMX 9 mg compared with placebo. [63]

Budesonide rectal foam was FDA approved in October 2014 and is indicated for the induction of remission in adults with active mild-to-moderate distal ulcerative colitis extending up to 40 cm from the anal verge. Approval was based on two randomized, placebo-controlled trials (N = 546) that showed that more participants who received the budesonide rectal foam achieved remission and a rectal bleeding score of 0 at 6 weeks of therapy than placebo. [64]

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Treatment of Acute, Severe Disease

Acute, severe ulcerative colitis (UC) (ie, >6 bloody bowel movements/day, with one of the following: fever >38°C [100.4°F], hemoglobin level < 10.5 g/dL, heart rate >90 bpm, erythrocyte sedimentation rate >30 mm/h, or C-reactive protein level >30 mg/dL) requires hospitalization and treatment with intravenous high-dose corticosteroids (hydrocortisone 400 mg/d or methylprednisolone 60 mg/d). A meta-analysis supports the use of glucocorticosteroids in inducing remission in acute severe ulcerative colitis. [65]

Alternative induction medications have been evaluated. Cyclosporine, tacrolimus, infliximab, adalimumab, and golimumab are often effective in bringing steroid-resistant disease under control. Infliximab has shown to be superior to placebo in inducing remission of moderate-to-severe ulcerative colitis. [66] These agents have not been compared in a randomized, controlled fashion, and therefore, one drug cannot be recommended over the others. They have all been associated with overwhelming sepsis.

A systematic review and meta-analysis comprising eight randomized controlled studies of biologics in patients with inflammatory bowel disease found that primary nonresponse to anti-tumor necrosis factor (anti-TNF) agents was associated with an inferior response to second-line non-TNF biologics, relative to therapy discontinuation owing to secondary loss of response after initial response or intolerance. [67]

Cyclosporine is effecive for inducing remission in severely active and refractory ulcerative colitis, with an efficacy equivalent to that of infliximab. [10] Tacrolimus is effective for inducing remission in active disease, but no long-term safety and efficacy data exist. [10] Cyclosporine and tacrolimus are both nephrotoxic and should not be used for long-term therapy. Infliximab requires the coadministration of an antimetabolite to limit the development of human anti-mouse antibody (HAMA).

In the Active Ulcerative Colitis Trial (ACT)-1 and ACT-2, colectomy incidence was found to be 10% for the infliximab group, as compared to 17% for the placebo group through 54 weeks, and additional benefits of infliximab included fewer colitis-related hospitalizations and surgeries/procedures. In these two randomized, double-blind, placebo-controlled trials, the benefit of infliximab induction and maintenance therapy in moderate to severe ulcerative colitis was demonstrated in 728 patients. [68]

In a systematic review of 76 randomized controlled trials as well as cohort, cross-sectional, and case-controlled studies (years 2000-2016) that evaluated the pharmacokinetics of infliximab and/or infliximab dose intensification strategies in the setting of acute severe ulcerative colitis, investigators noted an increased infliximab clearance in patients. [69] Moreover, it appeared that in some cohort studies, at least half of patients with acute severe disease showed clinical improvement from an infliximab dose-intensified regimen, whereas findings from case-controlled studies suggested that this type of regimen plus an additional 1-2 infusions in the first 3 weeks of therapy potentially led to up to an 80% reduction in the early (3-month) colectomy rate.

A more recent study found that accelerated clearance of infliximab was associated with treatment failure in those with corticosteroid-refractory acute ulcerative colitis. [70]  The investigators indicated that their findings support using accelerated infliximab induction regimens in those with corticosteroid-refractory acute disease that has failed conventional dosing regimens.

Adalimumab was approved by the FDA in September 2012 for ulcerative colitis unresponsive to immunosuppressants. Approval was based on two phase 3 clinical studies. Both studies enrolled patients who had moderate-to-severe active ulcerative colitis despite concurrent or prior treatment with immunosuppressants (ie, corticosteroids, azathioprine, 6-mercaptopurine). Clinical remission was achieved in each study by week 8 and maintained in the long-term maintenance study at week 52. [71, 72]

Golimumab was approved for induction and maintenance of ulcerative colitis in May 2013. In the Program of Ulcerative Colitis Research Studies Utilizing an Investigational Treatment (PURSUIT) trial, a significantly higher proportion of patients receiving induction treatment with subcutaneous administrations of golimumab 200 mg at week 0 and 100 mg at week 2, or golimumab 400 mg at week 0 and 200 mg at week 2, met the primary endpoint of clinical response at week 6 compared with the placebo (51.8%, 55%, and 29.7% of patients achieving clinical response, respectively [< 0.0001]). [73]

The FDA approved tofacitinib, a Janus kinase (JAK) inhibitor, in May 2018 for induction and maintenance of adults with moderately to severely active ulcerative colitis. [74] It is the first oral medication approved for long-term use for this condition. Approval was based on the OCTAVE phase 3, randomized, double-blind, placebo-controlled induction 1 and 2 trials (N = 1139). [74, 75] In the OCTAVE Induction 1 trial, remission at 8 weeks occurred in 18.5% of the tofacitinib group compared to 8.2% in the placebo group (P = 0.007); in the OCTAVE Induction 2 trial, remission occurred in 16.6% versus 3.6% (< 0.001). In addition, the OCTAVE Sustain trial reported remission at 52 weeks in 34.3% of the 5-mg tofacitinib group and 40.6% in the 10-mg tofacitinib group compared to 11.1% in the placebo group (P< 0.001 for both comparisons with placebo). [75]

Some evidence suggests that in carefully selected patients whose condition fails both steroids and either cyclosporine or infliximab, a crossover to the other of these second-line treatments may avoid colectomy in the short term (within 2 months). [76]

The long-term outcome in such patients is less clear, and further followup studies are required both to assess the frequency with which such rescued patients progress to colectomy and to compare overall outcomes in the longer term in such patients after crossover of second-line therapy compared with transition to colectomy after the first failure of second-line therapy.

Vedolizumab is a recombinant humanized monoclonal antibody that binds to α4β7 integrin. Integrins are proteins involved in regulating cellular movement including migration of leukocytes to the gut. Vedolizumab is indicated for moderate to severe ulcerative colitis 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. Approval was based on a large phase 3 clinical trial conducted to simultaneously evaluate vedolizumab for both ulcerative colitis and Crohn disease, and included several clinical studies involving 2700 patients in nearly 40 countries.

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 (< 0.001). [77]

For induction, other treatments have been proposed—but are not standard therapy—and include the following:

  • Antibiotics have been used as an adjunct to steroid therapy but have not altered outcomes. However, a systemic review and meta-analysis by Khan et al and evidence-based guidelines by the Japanese Society of Gastroenterology indicate that antibiotic therapy may induce remission in active ulcerative colitis. [10, 78] However, selection of the type and duration of antibiotics remains undetermined. [10]

  • Helminth ova have not been shown to be superior to placebo.

  • Heparin may promote epithelial repair but is not effective given current delivery systems.

  • Leukocytapheresis has shown some potential and is quite popular in Japan, where it has been used to induce remission [79] and prevent postoperative septic complications. [80] Confirmatory studies in adults [81] and pediatric patients [82] are very promising. Intensive therapy (two sessions weekly) provides more rapid induction of remission and a better remission rate for moderate to severe ulcerative colitis than weekly therapy. [10] However, it remains a resource-intensive treatment.

    A randomized, multicenter open trial that compared seven weekly sessions of granulocyte/monocyte apheresis (GMA) plus oral prednisone (40 mg/day and tapering) with prednisone alone in patients with active steroid-dependent ulcerative colitis found that although clinical relapse was delayed with GMA/prednisone, the proportion of steroid-free remissions in these patients did not increase. [83]

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Indications for Surgery

Historically, surgery has been viewed as definitive therapy for ulcerative colitis (UC). Indications for surgery in ulcerative colitis are varied. Failure of medical management is the most common indication for surgery.

Indications for urgent surgery in patients with ulcerative colitis include (1) toxic megacolon refractory to medical management, (2) fulminant attack refractory to medical management, and (3) uncontrolled colonic bleeding. Indications for elective surgery in ulcerative colitis include (1) long-term steroid dependence, (2) dysplasia or adenocarcinoma found on screening biopsy, (3) and the presence of disease for 7-10 years.

A retrospective study (2002-2013) of data from 758 patients who underwent ileal pouch-anal anastomosis for ulcerative colitis in a high-volume Canadian inflammatory bowel institution found this procedure to be safe and effective for surgical management of ulcerative colitis. [84] Four hundred sixty pelvic pouches were created in 2 stages, 285 in 3 stages, and 13 in nontraditional staged operations. The most common early, same hospital stay complications were pelvic abscess (17.8%), small bowel obstruction (17.7%), and wound infection (14.3%), whereas anal stricture and pouch fistula were the most common late, post-discharge complications. The investigators reported an overall 12.1% pouch leak rate. [84]

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Maintenance Therapy

Once remission has been achieved, maintenance therapy is recommended for all patients with ulcerative colitis (UC) to prevent relapse. Oral aminosalicylates are indicated for disease that responded to aspirin (acetylsalicylic acid [ASA]) or steroids. Aspirin preparations are effective for induction and maintenance of remission in ulcerative colitis; the efficacy of these preparations for preventing ulcerative colitis-associated colorectal cancer remains inconclusive. [10] Patients who do not continue with maintenance therapy experience high rates of relapse. Some patients are unable to maintain remission or are intolerant of 5-aminosalicylic acid (5-ASA) (mesalamine). Azathioprine and 6-mercaptopurine are alternatives with proven effectiveness for maintenance of remission, particularly for those who are steroid dependent or unable to maintain remission with 5-ASA preparations. [10] For patients who were induced with infliximab, maintenance therapy should continue with infliximab or azathioprine.

Anti-tumor necrosis factor (anti-TNF) agents are effective for induction of remission in steroid-refractory or steroid-dependent moderate to severe ulcerative colitis. [10] If golimumab was used for induction with a good response, monthly maintenance therapy should continue with golimumab. In the PURSUIT maintenance trial (rogram of lcerative Colitis esearch tudies tilizing an nvestigational reatment), patients responding to golimumab induction were randomized to receive golimumab or placebo for maintenance. Subcutaneous (SC) golimumab 100 mg every 4 weeks maintained a clinical response through week 54 in 51% of patients compared with 31% of patients taking placebo (< 0.001). [85]

Daily oral maintenance with tofacitinib may be considered if an adequate therapeutic response was observed with tofacitinib induction. In the OCTAVE Sustain trial (ral linical rials for tofcitinib in ulceratiVE  colitis), remission at 52 weeks occurred in 34.3% of the 5-mg tofacitinib group and 40.6% in the 10-mg tofacitinib group compared to 11.1% in the placebo group (< 0.001 for both comparisons with placebo). [75]

Corticosteroids may be used for induction of remission of active ulcerative colitis [10] and continued for up to 8 weeks; however, these agents have no efficacy for maintenance of remission and should not be used for this purpose. [10] A novel formulation of slow-release budesonide (Uceris) was approved by the FDA in January 2013. Approval was based on results from the CORE 1 (co lonic re lease budesonide) study that showed endoscopic improvement at 8 weeks, increased remission rates, and clinical improvement with budesonide 9 mg once daily. [86]

Probiotics also appear to be effective at maintaining remission. Escherichia coli strain Nissle 1917 has been compared with mesalazine and proved to be similarly effective. [87] Bio-Three, a commercially available probiotic supplement (Enterococcus T-110, C butyricum TO-A, B mesentericus TO-A) produced remission in 45% of patients tested with mild-to-moderate ulcerative colitis. [88] Trials of fish oil to produce or maintain remission have shown no benefit over placebo.

No specific diet restrictions are required for patients with ulcerative colitis. However, many patients with ulcerative colitis can have concurrent lactose intolerance. No specific diet can maintain remission. [10]

Elemental nutrition and parenteral nutrition have no primary therapeutic role in ulcerative colitis, although parenteral nutrition is often used in patients who are severely ill as effective nutritional support.

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Complications

Several complications have been reported after ileal pouch–anal anastomosis procedures in patients with ulcerative colitis (UC). The anastomotic leak rate is 7%-9%. [89] If anastomotic leak occurs, fecal diversion, percutaneous drain placement, or repeat surgery with removal or revision of the reservoir is required. Pelvic abscess, which frequently accompanies an anastomotic leak, occurs in about 5% of cases (reports vary from 0% to 25%). Among patients with a pelvic abscess, 26% require excision of the pouch. Only 5.9% of patients without an abscess have pouch failure that requires removal.

If the abscess is managed with diversion and drainage, the pouch may be spared. However, these patients have higher rates of long-term incontinence and pain compared with those without abscesses. [90] In patients who require pouch excision due to abscess, a gracilis muscle interposition flap has been used to maintain the anal canal and allow future attempts at pouch procedures. [91] Pouch-vesicle, pouch-vaginal, pouch-anal, and enterocutaneous fistulas occur with a frequency of about 1% each.

Outcomes of pouch procedures are classified as good to excellent in as many as 90% of patients. Stool frequency is less than five per day in as many as 74%. Difficulty with evacuation occurs in 20%. About 77% of patients require no dietary restrictions; the remaining patients have a lower stool frequency with a low-fat diet. [92] Complete incontinence is reported in only 2%. Bulk-forming agents are required in as many as 30%.

Sexual dysfunction, manifested by retrograde ejaculation or impotence, occurs in 3% of males. Although Meagher et al reported sexual dysfunction in only 6% of females, [93] Ogilvie et al reported that 47% of females have low Female Sexual Function Index (FSFI) scores, indicating sexual dysfunction. [94] Additionally, Cornish et al described a 25% incidence of sexual dysfunction manifested by dyspareunia or psychological aversion to intercourse for fear of stool leakage. [95] Their report also documented an increase in infertility from 8% preoperatively to 26% postoperatively.

Pouchitis

Pouchitis is defined as a clinical syndrome in which the patient has increased stool frequency, malaise, fever, or incontinence. This syndrome has a reported incidence of 40%-60% but usually responds to antibiotic therapy (ciprofloxacin or metronidazole is most frequently used). The risk of pouchitis increases with time; 18% of patients have pouchitis at 1 year, and 48% have pouchitis at 10 years. [93] Pouch dilatation and pouch-anal anastomotic stricture may lead to fecal stasis and predispose the patient to pouchitis. Patients without a pouch rarely develop pouchitis and have comparable stool frequency with time. Clostridium difficile and Clostridium perfringens have been disproportionately found in patients with ulcerative colitis after ileal pouch–anal anastomosis. Treatment of these infections has led to decreases in inflammation. [96, 97]

Toxic megacolon

Toxic megacolon occurs in less than 2% of cases and can be induced by hypokalemia, opiates, anticholinergics, and barium enemas. Patients are acutely ill. Conservative treatment can be tried for 24-48 hours with administration of intravenous (IV) fluids, IV steroids, antibiotics, and IV cyclosporine. Patients may eventually require a total colectomy.

Carcinoma

Carcinoma is a known complication of ulcerative colitis in the small group of patients who have had the disease for approximately 10 years. The cancer tends to be multicentric, atypical in its appearance, and rapidly metastasizing. The risk of colorectal cancer increases by 0.5%-1% per year. Regular surveillance is needed.

Although the incidence of colon adenocarcinoma is greatly reduced with total proctocolectomy and ileal pouch–anal anastomosis, it is not zero. The residual colonic mucosa is at risk for dysplasia and neoplastic transformation. [98]

Because of the increased risk of colorectal cancer, guidelines from the American College of Gastroenterology recommend that after 8-10 years of colitis, patients with ulcerative colitis should undergo annual or biannual surveillance colonoscopy with multiple biopsies at regular intervals. [31] The finding of high-grade dysplasia in flat mucosa, confirmed on review by an expert pathologist, is an indication for colectomy; the finding of low-grade dysplasia in flat mucosa may also be an indication for colectomy to prevent progression to a higher grade of neoplasia. [31]

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Long-Term Monitoring

In a study that aimed to identify a panel of markers associated with the long-term outcome of infliximab therapy for patients with refractory ulcerative colitis (UC) (median follow-up, 5 y), Arias et al confirmed that short-term clinical response and mucosal healing—as well as baseline levels of C-reactive protein (CRP) of 5 mg/L or less and albumin of 35 g/L or greater—were independent predictors of colectomy-free survival. [99] Moreover, infliximab levels over 2.5 μg/mL at week 14 of treatment predicted both relapse-free survival and colectomy-free survival. A combined risk panel that included clinical response, mucosal healing, and levels of perinuclear antineutrophil cytoplasmic antibodies (pANCA), CRP, and albumin identified patients at risk for disease relapse or colectomy. [99]

In patients with chronic pouch inflammation, villous hypertrophy and dysplasia may occur. Although dysplasia has never been found within the pouch of a pediatric patient, chronic inflammatory changes have been identified, leading to the supposition that dysplasia may develop. Yearly screening endoscopy has been recommended for the first 5 years after the procedure. In children who have chronic inflammatory changes in the pouch reservoir, annual screening endoscopy should be performed. If no inflammation is present, screening endoscopy may be performed every 2 years. [100]

Patients with extensive colitis or left-sided colitis with negative findings on screening colonoscopy should begin surveillance colonoscopy in 1-2 years. For patients with ulcerative colitis and primary sclerosing cholangitis, screening and subsequent surveillance colonoscopy should begin on an annual basis at the time of onset of primary sclerosing cholangitis.

Patients with proctosigmoiditis have no increased risk for colorectal cancer compared to the general population. However, these patients should be managed according to the current guidelines on colorectal cancer screening. If high-grade dysplasia or cancer is found, colectomy is performed. The management of low-grade dysplasia is controversial [101] ; however, most experts would recommend colectomy.

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Preventive Care

The American College of Gastroenterologists released their guideline on preventive care in inflammatory bowel disease (IBD) in 2017 [102] . Their preventive health maintenance recommendations are outlined below.

Strong recommendations

  • Patients with IBD (both ulcerative colitis and Crohn disease) should undergo screening for melanoma independent of the use of biologic therapy. IBD patients on immunomodulators (6-mercaptopurine or azathioprine) should undergo screening for nonmelanoma skin cancer (NMSC) while using these agents, particularly those older than 50 years. 
  • Patients with conventional risk factors for abnormal bone mineral density with ulcerative colitis and Crohn disease should undergo screening for osteoporosis with bone mineral density testing at the time of diagnosis and periodically after diagnosis.
  • Adults with IBD older than 50 years should consider vaccination against herpes zoster, including certain subgroups of immunosuppressed patients.

Conditional recommendations

  • Patients with conventional risk factors for abnormal bone mineral density with ulcerative colitis and CD should undergo screening for osteoporosis with bone mineral density testing at the time of diagnosis and periodically after diagnosis.
  • Adults with IBD should receive age-appropriate vaccinations before initiation of immune suppression when possible.
  • Household members of immunosuppressed patients can receive live vaccines with certain precautions.
  • All adult patients with IBD should undergo annual vaccination against influenza. Those on immunosuppressive therapies and their household contacts should receive the non-live trivalent inactivated influenza vaccine, but not the live inhaled influenza vaccine.
  • Adult patients with IBD receiving immunosuppressive therapy should receive pneumococcal vaccination with both the PCV13 and PPSV23, vaccines in accordance with national guidelines.
  • Adults with IBD should be assessed for prior exposure to varicella and vaccinated if naive before initiation of immunosuppressive therapy when possible.
  • Patients with IBD who are immunosuppressed and traveling to endemic areas for yellow fever should consult with a travel medicine or infectious disease specialist prior to travel
  • Adolescents with IBD should receive meningococcal vaccination in accordance with routine vaccination recommendations.
  • Vaccination against tetanus/diptheria, and pertussis (Tdap), hepatitides A and B (HAV, HBV, respectively); and human papillomavirus (HPV) should be administered as per Advisory Committee on Immunization Practice (ACIP) guidelines.
  • Women with IBD on immunosuppressive therapy should undergo annual cervical cancer screening.
  • Screening for depression and anxiety is recommended in patients with IBD.
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