inflammatory%20bowel%20disease
INFLAMMATORY BOWEL DISEASE
Inflammatory bowel disease consists of ulcerative colitis and Crohn's disease.
Ulcerative colitis is a diffuse mucosal inflammation limited to the colon while Crohn's disease is a patchy, transmural inflammation that occurs in any part of the gastrointestinal tract.
The ileum and colon are the most frequently affected sites.

Principles of Therapy

 PRINCIPLES OF THERAPY FOR ULCERATIVE COLITIS
  • Therapy decision depends on disease location, severity and presence of complications
  • Treatment decisions should be individualized based on patient preference, patient’s previous response and tolerance to therapy
  • Central features of management should include continuity of care, appropriate long-term follow-up and attention to general health concerns (eg physical, emotional and quality of life issues)
  • In addition to evaluation of the extent and activity, a global assessment of the patient should include attention to extraintestinal manifestations
  • Infection should be ruled out prior to treatment

Goals of Therapy

  • Treat active disease and maintain remission
  • Provide an improved quality of life
  • Decrease the need for long-term use of corticosteroids
  • Minimize risk of cancer and other treatment-related complications
  • Maintain good nutritional status

 

PRINCIPLES OF THERAPY FOR CROHN’S DISEASE

  • Therapy decision depends on disease site, pattern (inflammatory, stricturing, fistulating), severity, and presence of complications
  • Treatment decisions should be individualized based on patient’s previous response and tolerance to therapy; cost of the therapy should also be considered
  • Clinical evidence of improvement should be seen within 2-4 weeks and maximal improvement should be evident within 12-16 weeks
  • In patients with mild to moderate CD who do not respond, may try alternative treatment or may advanced to treatment for moderate to severe CD based on their clinical status
  • Infection should be ruled out or active inflammation due to CD confirmed prior to treatment
  •  For mild to moderate CD 2 approaches of treatment are recommended, although the merits of these strategies have not been extensively studied:
    • Step-up therapy: Starts with less potent medications associated with fewer side effects. Once initial medications are ineffective, more potent therapies (potentially more toxic) are used
    • Top-down therapy: Starts with more potent medications (eg immunosuppressants, biologic therapy) early in the course of the disease before patients become corticosteroid dependent and even before administration of corticosteroids

Goals of Therapy

  • To induce and maintain control of symptoms
  • To provide an improved quality of life
  • To minimize short- and long-term toxicity and complications

Pharmacotherapy (Active Mild-Moderate Distal Ulcerative Colitis)

  • Patients may be treated with either oral or topical medications
  • Some patients achieve maximum benefit from the combination of oral and topical therapy
  • Therapeutic effect of topical therapy is generally quicker and has less frequent dosing schedule than oral therapy
  • Choice of vehicle is determined by patient preference and proximal extent of disease
    • Suppositories can reach approximately 10 cm
    • Foam can reach approximately 15-20 cm
      • May be used if suppositories are not available
    • Enema can reach up to the splenic flexure

Aminosalicylates

  • Beneficial in achieving and maintaining remission
  • Effective in 40-80% of patients with effects generally seen in 2-4 weeks of therapy
  • Use of topical aminosalicylates is better than topical corticosteroids or oral aminoglycosides
  • Topical route can deliver much higher concentrations to the distal colon than oral compounds

Mesalazine

  • Preferred initial treatment for mild-moderate active proctitis
  • Alternative for patients who do not respond to or tolerate topical therapy
  • Combination of oral Mesalazine with topical Mesalazine is more effective than either treatment alone
    • Topical Mesalazine may still be given in patients refractory to oral aminosalicylates or topical corticosteroids
    • Mesalazine suppositories are effective in the treatment of proctitis and maintenance of remission
    • Mesalazine enemas are effective in inducing and maintaining remission in distal colitis
  • Topical Mesalazine and oral Mesalazine or topical steroid was found to be more successful in proctitis than when given alone
    • May also be used as a treatment strategy for dose increases in proctitis

Balsalazide, Olsalazine

  • When combined with topical Mesalazine are effective 1st-line agents

Sulfasalazine

  • Has a higher incidence of side effects compared to newer aminosalicylates
  • Sulfapyridine component is absorbed and may cause side effects in 15-30% of patients
  • Majority of patients who are intolerant of Sulfasalazine are able to tolerate other aminosalicylates
  • Patients on long-term Sulfasalazine should be advised to take folic acid supplementation

Corticosteroids

  • Systemic absorption is lesser as compared with oral forms
  • Provide adequate suppression of inflammation with rapid relief of symptoms
  • Topical corticosteroids (eg Hydrocortisone foam or enema) are effective in acute therapy of distal colitis but have not been proven effective in maintaining remission
  • Budesonide enema seems to be as effective as Hydrocortisone but with fewer side effects
    • Should be reserved for patients who failed Mesalazine enemas
  • Less effective than topical Mesalazine and generally reserved for patients who cannot tolerate topical Mesalazine

Patients Not Responding to Therapy

Corticosteroids (Oral)

  • Oral Prednisolone or once-daily Budesonide should be considered if patient fails to respond to a combination of oral aminosalicylate and topical Mesalazine or topical corticosteroids
  • Dose may be reduced over an 8-week period once patient responds to therapy
  • There is no evidence that supports chronic corticosteroid therapy as an effective agent for maintenance of remission

Tacrolimus

  • Recommended for patients with moderately active UC not responding to steroid therapy

Pharmacotherapy (Active Mild-Moderate Extensive Ulcerative Colitis)

  • If inflammation extends beyond the reach of topical therapy, oral therapy is required
  • Oral therapy may be combined with topical therapy since this may benefit some patients with rectal symptoms

Aminosalicylates (Oral)

  • Considered 1st-line of treatment

Mesalazine

  • Combination of topical and oral Mesalazine was found to be more successful in achieving clinical remission at 8 weeks, compared to oral Mesalazine alone

Sulfasalazine

  • Traditionally, the agent of choice for mild-moderate extensive colitis
  • Response is dose-related with up to 80% of patients who receive daily doses of 4-6 g manifesting clinical remission or significant clinical improvement within 4 weeks
    • These higher doses are related to increased side effects

Patients Not Responding to 1st-Line Agents

Corticosteroids (Oral)

  • Eg Prednisolone or once-daily Budesonide
  • Reserved for patients who are refractory to oral aminosalicylates with or without topical therapy and for patients with troubling symptoms demanding rapid improvement
  • Once remission is achieved, gradually taper the dose usually over 8 weeks
  • Long-term use is associated with serious and potentially irreversible side effects

Tacrolimus

  • Recommended for patients with moderately active UC not responding to steroid therapy

Thiopurines

  • Eg Azathioprine, Mercaptopurine
  • End metabolite, thiopurine, exerts an antiproliferative effect on mitotically active lymphocyte populations
  • May have direct anti-inflammatory properties by inhibiting cytotoxic T cell and natural killer cell function and inducing apoptosis of T cells
  • Effective for patients who do not respond to oral corticosteroids but not severely ill to require IV therapy
  • Recommended in patients with chronic active corticosteroid-dependent disease
  • Azathioprine has slow onset of action with 3-6 months in order to observe optimal effect

TNF Inhibitors

  • Eg Infliximab, Adalimumab, Golimumab
  • Recommended for patients with moderately active UC who are steroid-refractory or steroid-dependent despite adequate doses of thiopurines
  • Golimumab may be used to treat moderate-severe UC
Other Immunosuppressants
  • Vedolizumab and Basiliximab have shown to be beneficial for moderately active UC

Pharmacotherapy for Severe Ulcerative Colitis

Pharmacological Therapies

Corticosteroid (IV)

  • Mainstay of therapy in patient with severe colitis refractory to maximal oral treatment or who presents with toxicity
  • Failure to demonstrate significant improvement with IV corticosteroids within 3-5 days is an indication for either colectomy or treatment with IV Cyclosporin or Infliximab
    • Long-term efficacy of Infliximab, in this setting, is still to be determined
  • Long-term remission is significantly enhanced with the addition of long-term maintenance with Mercaptopurine
  • Less severely ill patients usually respond to IV corticosteroids within 7-10 days
Ciclosporin
  • Diminishes cytokine production and exerts an antiproliferative effect on lymphocytes
  • IV Ciclosporin should be considered 1st-line rescue therapy if there is no improvement after 3-5 days of intensive IV corticosteroid use, ie use in acute corticosteroid-refractory severe colitis
  • Suitable to patients who are not psychologically prepared for colectomy
  • Surgery is recommended if no response is seen in 7-10 days
  • For patients with good response who have not been previously treated with Azathioprine or Mercaptopurine, may continue Ciclosporin for 3-4 months while introducing Azathioprine or Mercaptopurine
Tacrolimus
  • Recommended as a therapy option for patients with steroid-refractory UC
  • Studies have shown that patients with severe UC are able to survive longer without colectomy when treated with Tacrolimus

Infliximab

  • A TNF inhibitor, Infliximab may be used in patients with severe UC, refractory to maximal oral therapy with Prednisolone, oral aminosalicylates and topical agents, who do not require urgent hospitalization
  • Surgery is recommended if no response is seen within 4-7 days
  • Not recommended as maintenance therapy due to low corticosteroid-free remission rate after 1 year
Vedolizumab
  • May be given to patients with moderately to severely active UC in whom conventional therapy or TNF-alpha antagonists could not be tolerated or were ineffective

Maintenance of Ulcerative Colitis Remission

  • Once the acute UC attack is controlled, a life long maintenance regimen is usually required especially if the patient suffers left-sided, or extensive or relapsing disease
  • Medication discontinuation may be considered in those with distal disease who have been in remission for 2 years and are averse to the medication
    • There is some evidence that maintenance therapy reduces the risk of colorectal cancer and this should be considered
  • Patients in full remission after 4 years may consider cessation of therapy, although a small benefit may persist even after 6 years

Aminosalicylates (Oral)

  • All aminosalicylates are effective in reducing relapses
  • Initial therapy includes combination of oral Mesalazine or Sulfasalazine and Mesalazine or corticosteroid enemas
    • Combination of oral and topical agents is more effective than oral drug alone
  • Balsalazide and Mesalazine should be considered 1st-line agents over Sulfasalazine because of lesser side effects

Corticosteroids (Oral)

  • Generally ineffective in maintaining remission
  • Should not be used chronically, doses are tapered once clinical improvement is observed in patients
  • Budesonide may be used for short term (ie 3 months) maintenance of remission

Thiopurines

  • Eg Azathioprine, Mercaptopurine
  • Effective in maintaining remission regardless of disease distribution
  • Considered 1st-line steroid-sparing agents for steroid dependent patients
  • May be used as maintenance therapy for patients with the following conditions:
    • Severe relapse or frequently relapsing disease
    • Requires ≥2 corticosteroids courses within 12 months
    • Relapses within 6 weeks of corticosteroid withdrawal
    • Severe UC who improved with Ciclosporin for induction of remission

TNF Inhibitors

  • Eg Infliximab, Adalimumab
  • Have been found to be effective in inducing response and maintaining remission
Vedolizumab
  • Has also been found to be effective in inducing response and maintaining remission

Probiotics

  • Eg Escherichia coli strain Nissle, VSL#3, Saccharomyces boulardii, Bifido-fermented milk
  • Escherichia coli strain Nissle is recommended as an alternative to Mesalazine for the maintenance of remission of UC
  • Have shown to be therapeutically equivalent to Mesalazine in preventing relapses in patients with inactive UC and for inducing remission in patients with active UC

Pharmacotherapy (Active Mild-Moderate Ileal/Colonic Crohn's Disease)

Therapy with oral medications is appropriate for patients with mild to moderate CD

Aminosalicylates

  • Its use in mild to moderately active CD is controversial, with studies producing mixed results
  • Some experts do not recommend aminosalicylates, except Sulfasalazine, for maintenance of remission of CD
  • Recommended for patients intolerant to glucocorticosteroids or in whom it is contraindicated
  • May be used for a inflammatory exacerbation for a 12-month period
  • Has less adverse effects as compared to corticosteroids and Budesonide

Mesalazine

  • Oral Mesalazine, used at high dose, may be sufficient initial therapy
  • Topical Mesalazine may be used in left-sided colonic CD of mild-moderate activity
  • New evidence suggests that oral Mesalazine is less effective compared to Budesonide or other conventional corticosteroids

Sulfasalazine

  • Effective for active colonic disease
  • Sulfasalazine combined with corticosteroid was not found to be more effective than corticosteroid alone for the induction or remission
  • Patients should be given folic acid while being treated with Sulfasalazine

Antibiotics

  • May be given in CD patients since microorganisms are considered potential trigger of CD
  • May be used in the treatment of CD complications (eg presence of fistulas, perianal disease, bacterial colonizations in colonic strictures)
  • Patients on antibiotics are at increased risk of developing C difficile-associated diarrhea

Metronidazole

  • Effective but considered only as an alternative agent because of potential adverse effects
    • May be considered in selected patients with colonic disease (ie ileocolitis and colitis), those with resistant disease or in patients who wish to avoid corticosteroids
  • May be used in selected patients unresponsive to Sulfasalazine

Ciprofloxacin

  • Commonly used in combination with other agents in the treatment of CD
  • As monotherapy, it is not consistently effective for the treatment of CD

Corticosteroids

  • Oral corticosteroids remain the mainstay of treatment esp in patients who are unresponsive to aminosalicylates or antibiotics, or for selected patients who present with more severe initial symptoms
  • Oral corticosteroids should not be used for long-term management due to side effects
  • One trial demonstrated that combination of Sulfasalazine and Prednisolone has better effects than either agent alone
  • Oral Budesonide is recommended as the 1st-line agent in treating active ileitis or right-sided CD; Budesonide is not to be used for severe CD or exacerbations
    • Has been shown to be less effective in inducing remission

Thiopurines

  • Eg Azathioprine, Mercaptopurine
  • Recommended as additional therapy to induction therapy with corticosteroids or Budesonide given the following conditions:
    • ≥2 exacerbations during the 12-month period
    • Tapering of steroid dose is not recommended

Methotrexate

  • Recommended as induction therapy to patients intolerant or unresponsive to thiopurine therapy, given the following conditions:
    • ≥2 exacerbations during the 12-month period
    • Tapering of steroid dose is not recommended

Patients Not Responding to Initial Therapy

  • Patients should be evaluated within several weeks of starting initial therapy
  • In patients who do not respond, may try a different agent for mild to moderate CD or may advance the treatment to medications used for moderate-severe CD
  • In patients who do not respond completely to 1st-line therapy, may try symptomatic treatment with antidiarrheal agents

Refractory to Therapy

  • Defined as patients with CD who relapse while on treatment, who fail to respond to aminosalicylates, antibiotics or corticosteroids, or who fail to be tapered off from corticosteroids
  • May be treated with immunosuppressants or biologic agents

Pharmacotherapy (Active Moderate-Severe Ileal/Colonic Crohn's Disease)

Chronic active and steroid-dependent disease

  • Steroid refractory disease: Active disease despite adequate dose and duration of Prednisolone
  • Steroid dependent: Relapse when the steroid dose is reduced <20 mg/day or within 6 weeks of stopping steroids

Anti-Tumor Necrosis Factor (Anti-TNF)

Adalimumab

  • Recommended as treatment option in patients with severely active CD, who are unresponsive to treatment despite adequate treatment with conventional therapy
  • May be given as monotherapy if patient is intolerant to combination with corticosteroids
  • Should be given as a planned course of treatment until treatment failure, including the need for surgery or until 12 months

Certolizumab

  • Recommended as treatment option in patients with moderate to severely active CD, who do not respond to conventional therapy, or who are intolerant of or have contraindications to conventional therapy

Infliximab

  • Infliximab monotherapy and combined therapy with Azathioprine are superior than Azathioprine alone in the treatment of patients with moderate to severely active CD who are unresponsive to 1st-line agents (ie Mesalazine and/or corticosteroids)
  • May also be given in patients who are intolerant of or have contraindications to conventional therapy
  • Should be given as a planned course of treatment until treatment failure, including the need for surgery, or until 12 months
  • Avoid in patients with obstructive symptoms

Natalizumab

  • Effective in patients with moderate to severely active CD who are unresponsive to or are unable to tolerate the conventional CD treatment regimen

Thiopurines

  • Eg Azathioprine, Mercaptopurine
  • May be used as adjunctive therapy and as steroid sparing agents
  • Due to slow onset of action, these are not used as sole therapy

Budesonide

  • Oral Budesonide is marginally less effective than Prednisolone but should be considered in those with isolated ileocecal disease with moderate disease
  • Recommended for patients with ileocecal or right-sided colonic disease who are intolerant to conventional corticosteroids

Methotrexate

  • Effective for chronic active disease and many people respond to oral therapy and allows for steroid tapering in steroid-dependent patients
  • Usual dose for steroid dependent patients: 25 mg IM once weekly

Prednisolone

  • Oral Prednisolone may be used in mild-moderate disease that has failed to respond to oral Mesalazine or in those with moderate-severe ileocolonic CD
  • Prednisolone should be reduced gradually according to severity and patient response, generally over 8 weeks
    • More rapid reduction is associated with early relapse
Vedolizumab
  • May be given to patients with moderately to severely active CD in whom conventional therapy or TNF-alpha antagonists could not be tolerated or were ineffective

Pharmacotherapy (Active Perianal Crohn's Disease)

  • Perianal disease is often associated with CD located elsewhere in the GI tract which should be treated appropriately
  • The initial aim should be to treat active disease and sepsis
  • The presence of acute suppuration is an indication for surgical drainage with or without placement of setons
  • Nonsuppurative, perianal fissuring or chronic fistulization may be treated medically with antibiotics or immunosuppressants
  • Antibiotics are used in the treatment of CD complications (eg perianal disease, presence of fistulas, bacterial colonizations in colonic stricture)

Metronidazole

  • Considered 1st-line therapy for simple perianal fistulae
  • May be used alone or in combination with Ciprofloxacin for nonsuppurative perianal complications
  • Continuous therapy may be necessary to prevent recurrent drainage
    • Safety of long-term use has not been established
    • Monitor patient for evidence of peripheral neuropathy

Azathioprine or Mercaptopurine

  • May be effective for simple perianal fistulae or enterocutaneous fistulae when distal obstruction and abscess have been ruled out

Infliximab

  • Has limited use in the closure of CD fistulae that have not responded to prior therapy with antibiotics, corticosteroids or other immunomodulators
  • Should be used as part of an overall plan that includes immunosuppression and surgery

Tacrolimus

  • Recommended for treatment of fistulizing CD

Pharmacotherapy (Severe to Fulminant Crohn's Disease)

Hospital Management for Severe to Fulminant Crohn's Disease

  • Patient should be hospitalized if they continue to suffer CD related symptoms despite oral corticosteroids or immunosuppressants (Infliximab, Adalimumab), or those who present with high fever, vomiting, evidence of obstruction, cachexia, rebound renderness or evidence of abscess


Pharmacological Therapies
Antibiotics

  • If an inflammatory mass is present, broad-spectrum antibiotics should be given along with IV corticosteroids

Ciclosporin (IV)

  • May be an option for patients who do not respond to parenteral corticosteroids
  • Faster onset of action compared with Azathioprine, Mercaptopurine and Methotrexate
  • Relapses frequently occur with discontinuance of use

Corticosteroids (IV)

  • May be started as a continuous infusion once abscess has been excluded or if the patient has been receiving oral corticosteroids

Maintenance of Crohn's Disease Remission

  • Efficacy of maintenance therapy depends on whether remission was achieved by medication or surgery, risk of relapse and site of the disease
  • Maintenance of remissions has been shown to reduce hospitalizations and need for surgery beyond 1 year, as well as improve the quality of life of patients
  • Consider escalating maintenance therapy in relapsing patients to avoid disease progression
  • Smoking cessation may be the most important factor in maintaining remission

Aminosalicylates

Mesalazine

  • May be considered for long-term maintenance therapy, although with limited benefit
  • Should be considered after ileocolonic resections to reduce the likelihood of recurrence

Sulfasalazine

  • Has inconsistent maintenance benefits after medical inductive therapy

Antibiotics

  • Limited data on its effect for maintenance of remission
  • Metronidazole may be given after ileocolonic resections to reduce the likelihood of recurrence

Corticosteroids

  • Conventional corticosteroids should not be used for long-term maintenance of remission

Budesonide

  • May be effective for short-term maintenance of remission (ie 3-6 months) in ileal and/or right colonic disease

Thiopurines

  • Eg Azathioprine, Mercaptopurine
  • Recommended after ileocolonic resections to reduce the likelihood of recurrence
  • Considered 1st-line agents for patients with the following conditions:
    • Severe relapse or frequently relapsing disease
    • Requires ≥2 corticosteroids courses within 12 months
    • Relapses within 6 weeks of corticosteroids withdrawal
  • May be used as monotherapy for patients previously given conventional corticosteroids or those who have been given other induction therapy options aside from thiopurines, or those who have achieved sustained remission on combination treatment
  • Azathioprine is effective for patients whose active disease responded to Infliximab in steroid-naive patients
  • Proven to be effective in maintaining remission regardless of disease distribution

Methotrexate

  • Recommended as maintenance therapy for remissions of CD in patients:
    • Whose active disease responded to Methotrexate
    • Who are intolerant or unresponsive to Azathioprine/Mercaptopurine therapy
    • Who have contraindications against Azathioprine/Mercaptopurine (ie deficient TPMT activity, history of pancreatitis)
  • May be considered in those who are intolerant of or who have failed from Azathioprine or Mercaptopurine therapy
  • Potential toxicity and alternative options, including surgery need to be discussed with patient before deciding on use
Anti-Tumor Necrosis Factor (Anti-TNF)
  • Considered in patients with poor prognostic factors or severe disease course

Infliximab

  • Best used as part of treatment strategy including other options
  • Infliximab monotherapy and combined therapy with Azathioprine are superior than Azathioprine alone for maintenance of patients with moderate to severely active CD who are unresponsive to 1st-line agents (ie Mesalazine and/or corticosteroids)
  • Should be considered after ileocolonic resections to reduce the likelihood of recurrence
  • Scheduled infusions have been effective at maintaining remissions in both luminal and fistulizing CD
    • Scheduled maintenance therapy (eg every 8 weeks) is less immunogenic and has been associated with prolonged mucosal healing, compared to episodic dosing

Adalimumab

  • Recommended as a long-term regimen used to prevent relapses in patients who were responsive to induction therapy with Adalimumab
  • Disease reassessment is recommended for patients undergoing Adalimumab therapy for >1 year

Other Immunosuppressants

  • Certolizumab, Natalizumab and Vedolizumab are effective for maintaining remissions
Digital Edition
Asia's trusted medical magazine for healthcare professionals. Get your MIMS Gastroenterology - Malaysia digital copy today!
DOWNLOAD
Editor's Recommendations
Most Read Articles
01 May 2014

New drug applications approved by US FDA as of 15-30 May which includes New Molecular Entities (NMEs) and new biologics. It does not include Tentative Approvals. Supplemental approvals may have occurred since the original approval date.

12 Apr 2017
Patients with fibromyalgia syndrome (FMS) are at an increased risk of peptic ulcer disease (PUD), a new study shows.
08 May 2017
Transabdominal bowel wall ultrasonography shows utility in monitoring disease activity in patients with active Crohn’s disease (CD), according to a study. The imaging technique is ideal for evaluating early transmural changes in disease activity, in response to medical treatment.
01 Jun 2015
A mixture of the flavonoids diosmin, troxerutin, and hesperidin is safe and effective for the symptomatic management of patients with acute haemorrhoidal disease, a prospective, randomised, triple-blind, controlled trial revealed.