Inflammatory%20bowel%20disease Treatment

Ulcerative Colitis 

• Therapy decision depends on disease location, severity, pattern of disease and presence of complications
  • 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, psychosocial, 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 (eg CMV, C difficile, other bacteria, parasites) should be ruled out prior to UC treatment and be treated accordingly

Goals of Therapy

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

Crohn's Disease

• Therapy decision depends on disease site, pattern (inflammatory, stricturing, fistulating), severity, and presence of complications
  • 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 advance to treatment for moderate to severe CD based on their clinical status
• Infection (eg CMV, C difficile, food poisoning) 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

• 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 aminosalicylates
• Topical route can deliver much higher concentrations to the distal colon than oral compounds
  • Topical preparations can also provide quicker response time compared to oral preparations
  • There is no difference between foam and liquid enemas in the induction of remission or endoscopic healing
• Aminosalicylate enema in combination with oral Mesalazine is the recommended initial treatment for mild to moderately active left-sided UC, and is found to be more effective than oral or topical aminosalicylates, or topical steroids alone

Mesalazine 

• Topical Mesalazine is the 1st-line treatment for mild to moderately active proctitis
  • Suppository is the preferred initial treatment for mild to moderately active proctitis because the drug is delivered specifically to the rectum and is better retained
  • Mesalazine suppositories are effective in the treatment of proctitis and maintenance of remission
  • Foam or enemas are an alternative for mild to moderately active proctitis
• Topical Mesalazine is more effective than topical steroids in mild to moderately active proctitis and active left-sided UC
• Combination of topical Mesalazine and oral Mesalazine 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
  • Combination of Beclomethasone dipropionate and Mesalazine enemas produced significantly better clinical, endoscopic, and histological improvement compared to either agents alone
• Combination of oral Mesalazine with topical Mesalazine is the 1st-line therapy for mild to moderately active left-sided UC
  • Combination of topical Mesalazine and oral Mesalazine is more effective for active distal colitis compared to either agent alone
  • Topical Mesalazine may still be given in patients refractory to oral aminosalicylates or topical corticosteroids
  • Mesalazine enemas are effective in inducing and maintaining remission in distal colitis
• Once-daily dosing of oral Mesalazine is recommended over multiple times per day dosing in patients with mild-moderate UC

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
  • Oral Sulfasalazine is as effective as oral Mesalazine but oral Mesalazine is better tolerated
• Patients on long-term Sulfasalazine should be advised to take folic acid supplementation

Corticosteroids

• Systemic absorption and side effects are lesser as compared with oral forms
• Provide adequate suppression of inflammation with rapid relief of symptoms
• Topical steroids are a treatment option for patients with proctitis with inadequate response or intolerant to topical and oral Mesalazine
• 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 rectal foam was shown to induce remission by week 6
• 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 Initial Therapy

• Patients with refractory proctitis may be treated with systemic corticosteroids, immunosuppressants, and/or biologicals

Corticosteroids (Oral)

• Systemic corticosteroids may be used in patients with mildly active left-sided UC who do not respond to Mesalazine
• Addition of oral steroids are recommended when patient's symptoms deteriorate, when there is persistence of rectal bleeding beyond 10-14 days, or when sustained relief from all symptoms has not been achieved after 40 days of appropriate Mesalazine therapy
• 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
  • Oral once-daily Budesonide may be used in patients with mild to moderately active left-sided UC who are intolerant or refractory to optimized aminosalicylate therapy
• Oral Beclomethasone dipropionate may be used as an alternative to Prednisolone in patients with mild to moderately active UC and refractory to Mesalazine
• 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

• 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
• Combination of oral Mesalazine with aminosalicylate enema is the recommended initial treatment for mild to moderately active extensive UC

Sulfasalazine

• Traditionally, the agent of choice for mild to moderate extensive colitis
• Has similar efficacy with Mesalazine but Mesalazine has a better safety profile
• 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 Initial Therapy

• In patients with moderate to severe UC, TNF inhibitors, Ustekinumab or Vedolizumab may be combined with thiopurines or Methotrexate rather than biologic or thiopurine monotherapy 

Corticosteroids (Oral) 

• Eg Prednisolone, once-daily Budesonide or Beclomethasone dipropionate
• Reserved for patients who are refractory to oral aminosalicylates with or without topical therapy and for patients with troubling symptoms demanding rapid improvement
• May be used in patients with mildly active extensive UC unresponsive to Mesalazine
• Effective in the induction of remission in patients with moderate to severely active UC who are refractory to Mesalazine or Sulfasalazine, and in patients who have responded initially to IV corticosteroids for acute severe disease
• Once remission is achieved, gradually taper the dose usually over 8 weeks
• Long-term use is associated with serious and potentially irreversible side effects
• IV steroids are recommended for patients with moderately active UC and refractory to oral steroids

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
• Recommended in patients with chronic active corticosteroid-dependent disease
• Effective for patients who do not respond to oral corticosteroids but not severely ill to require IV therapy
• Due to Azathioprine's relatively slow onset of action, it may be appropriate to start it in patients with active UC where maintenance therapy with Azathioprine is considered, but only when given together with an effective induction agent

Tumor Necrosis Factor (TNF) Inhibitors

• Eg Infliximab, Adalimumab, Golimumab
• Recommended for patients with moderately active UC who are refractory to thiopurines
  
  • Combination of Infliximab with Azathioprine is more effective compared to Infliximab alone
• Also recommended for patients with moderately active UC who are steroid-refractory or steroid-dependent despite adequate doses of thiopurines 
• Effective in obtaining and maintaining steroid-free remission in patients receiving corticosteroids at baseline
• TNF inhibitors are recommended for induction of remission in patients with moderate to severe UC who are intolerant to or have inadequate response to conventional treatment
  • Infliximab may be used for induction of remission in patients with moderate to severe UC who are naive to biologic agent therapy

Tofacitinib

• Treatment option for patients with moderate to severe UC refractory or intolerant to steroids, thiopurines and anti-TNF
• May be used for induction of remission in patients with moderate to severe UC previously treated with Infliximab, especially primary non-responders to induction therapy

Other Immunosuppressants 

• Basiliximab, Ustekinumab and Vedolizumab have shown to be beneficial for moderately active UC
• Ustekinumab may be used for the induction of remission in patients with moderate to severe UC who are intolerant to or have inadequate response to conventional treatment
  • May also be used for induction of remission in patients with moderate to severe UC previously treated with Infliximab, especially primary non-responders to induction therapy 
• Vedolizumab is recommended for induction of remission in patients with moderate to severe UC who are refractory or intolerant to thiopurines or to anti-TNF
  • May also be used for induction of remission in patients with moderate to severe UC who are naive to biologic agent therapy
• Ozanimod is an oral sphingosine 1-phosphate receptor modulator indicated for the treatment of moderately to severely active UC in adults

Corticosteroid (IV)

• Eg Methylprednisolone, Hydrocortisone 
• Mainstay of therapy in patient with severe colitis refractory to maximal oral treatment or who presents with toxicity
• IV Methylprednisolone at 40-50 mg/day may be used rather than other higher-dose IV corticosteroids
• Less severely ill patients usually respond to IV corticosteroids within 7-10 days
• 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 remission is significantly enhanced with the addition of long-term maintenance with Mercaptopurine

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
• Used as an alternative to corticosteroids in patients with adverse events due to steroids including patients with poorly controlled diabetes, with concomitant osteoporosis, or patients susceptible to steroid psychosis
• Suitable to patients who are not psychologically prepared for colectomy
• Surgery is recommended if no response is seen in 4-7 days of salvage therapy
• 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
• Should be avoided in patients with low cholesterol or magnesium due to increased incidence of neurological side effects

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
• Effective salvage therapy in patients with severe UC and refractory to IV corticosteroids
• Combination with Azathioprine has shown a synergistic effect
• Surgery is recommended if no response is seen within 4-7 days of salvage therapy
• Not recommended as maintenance therapy due to low corticosteroid-free remission rate after 1 year

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

Vedolizumab 

• May be given to patients with moderately to severely active UC in whom conventional therapy or TNF inhibitors could not be tolerated or were ineffective

• 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 CRC 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
• Choice of maintenance therapy is determined by:
  • Treatment used to induce remission during the most recent flare 
  • Extent of disease
  • Course of the disease (frequency and intensity of flares)
  • Severity of the most recent flare
  • Failure and adverse effects of previous maintenance therapy
  • Safety of maintenance therapy
  • Cancer prevention
• Stepwise escalation of maintenance treatment is achieved by:
  • Increasing dose of oral or rectal aminosalicylates
  • Addition of thiopurine
  • Addition of anti-TNF
  • Addition of immunosuppressant

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
  • Combination of oral and rectal Mesalazine may be a 2nd-line maintenance treatment
• Balsalazide and Mesalazine should be considered 1st-line agents over Sulfasalazine because of lesser side effects
• Mesalazine is the 1st-line maintenance treatment in patients responding to Mesalazine or steroids
• Rectal Mesalazine is the 1st-line maintenance therapy in proctitis and alternative therapy in left-sided colitis
• Long-term maintenance therapy with Mesalazine is recommended to reduce the risk of developing CRC

Corticosteroids (Oral)

• Generally ineffective in maintaining remission
• Should not be used chronically, doses are tapered over 60 days 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
• Recommended for patients with mild to moderately active UC who experienced early or frequent relapse with optimal dose of Mesalazine or intolerant of Mesalazine, patients with steroid-dependent disease, and patients responsive to Ciclosporin or Tacrolimus
• May be used as maintenance therapy for patients with the following conditions:
  
  • Severe relapse or frequently relapsing disease
  • Requires ≥2 corticosteroid courses within 12 months
  • Relapses within 6 weeks of corticosteroid withdrawal
  • Severe UC who improved with Ciclosporin for induction of remission

TNF Inhibitors

• Eg Adalimumab, Golimumab, Infliximab
• Recommended for maintaining remission in patients with moderate to severe active UC who responded to induction treatment with the same drug
• Have been found to be effective in inducing response and maintaining remission with or without thiopurines
  • Consider combination therapy with a thiopurine in patients who have failed treatment with ≥1 TNF inhibitors

Tofacitinib

• Recommended for maintenance of remission in patients with moderate to severe UC who were responsive to induction therapy with Tofacitinib 
• Can be used in inducing response and maintaining remission in patients who are unresponsive to TNF inhibitors

Ustekinumab

• Recommended for maintenance of remission in patients with moderate to severe UC who were responsive to induction therapy with Ustekinumab

Vedolizumab 

• Has also been found to be effective in inducing response and maintaining remission in patients with moderate to severe UC

Ozanimod

• May be used for induction and maintenance therapy in patients with moderately to severely active UC

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

• 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 an inflammatory exacerbation for a 12-month period
• Has less adverse effects as compared to corticosteroids and Budesonide

Mesalazine

• Oral Mesalazine has not consistently demonstrated efficacy in inducing remission in CD and is not recommended as initial therapy
• Topical Mesalazine may be used in left-sided colonic CD of mild to 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 septic 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

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

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

Corticosteroids

• Oral corticosteroids remain the mainstay of treatment especially 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
• Budesonide is recommended for the induction of symptomatic remission in patients with active mild to moderate CD of the ileum and/or ascending colon

Thiopurines

• Eg Azathioprine, Mercaptopurine
• Considered as additional therapy to induction therapy with corticosteroids or Budesonide given the following conditions:
  • ≥2 inflammatory exacerbations in a 12-month period
  • Tapering of steroid dose cannot be done
• Consider thiopurine methyltransferase (TPMT) testing prior to using Azathioprine or Mercaptopurine in CD

Methotrexate

• Considered as additional therapy to induction therapy with corticosteroids or Budesonide in patients intolerant or unresponsive to thiopurine therapy, given the following conditions:
  • ≥2 inflammatory exacerbations in a 12-month period
  • Tapering of steroid dose cannot be done

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 to severe CD
• In patients who do not respond completely to 1st-line therapy, may try symptomatic treatment with antidiarrheal agents
  • Active symptoms of patients with low risk of progression may be treated with antidiarrheals and dietary manipulation with careful monitoring of symptoms

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

Anti-Integrin Agents

Natalizumab

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

Vedolizumab

• May be given for induction of response and remission in patients with moderately to severely active CD in whom conventional therapy and/or anti-TNF agents could not be tolerated or were ineffective 
  • May be given with or without an immunomodulator 
• Should be given as a planned course of treatment until treatment failure, including the need for surgery, or until 12 months after treatment initiation, whichever is shorter 

Corticosteroids

• Systemic corticosteroids are used initially for the induction of clinical response and remission 
• Oral corticosteroids (Prednisone or Methylprednisolone) can be used for short-term treatment of signs and symptoms of moderate to severely active CD, while IV corticosteroids can be used for more severe disease

Prednisolone

• Oral Prednisolone may be used in mild to moderate disease that has failed to respond to oral Mesalazine or in those with moderate to 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

Steroid Treatment Response

• Steroid-dependent: Inability to reduce dose to <10 mg of Prednisolone equivalent within 12 weeks of starting or relapse within 12 weeks of stopping steroids
• Steroid-refractory: Active disease despite adequate dose and duration of Prednisolone, ie up to 1 mg/kg/day for 4 weeks

Methotrexate

• Effective for chronic active disease and allows for steroid tapering in steroid-dependent patients
• May be used as adjunctive therapy and as steroid-sparing agent 
• Due to slow onset of action, it is not effective in the short-term induction of active symptomatic disease

Thiopurines

• Eg Azathioprine, Mercaptopurine
• May be used in patients who remain symptomatic despite previous or current corticosteroid therapy
• May be used as adjunctive therapy and as steroid-sparing agents
• Due to slow onset of action, these are not effective in the short-term induction of active symptomatic disease

TNF Inhibitors

Adalimumab

• Recommended as treatment option in patients with moderately to severely active CD who are unresponsive to treatment despite adequate treatment with conventional therapy (corticosteroids, thiopurines, Methotrexate)
• 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 (corticosteroids, thiopurines, Methotrexate), or who are intolerant of or have contraindications to conventional therapy

Infliximab

• Combination therapy with Azathioprine is superior than either agents alone in the treatment of patients with moderate to severely active CD who are unresponsive to 1st-line agents (corticosteroids, thiopurines, Methotrexate)
• 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

Biosimilar Anti-TNF Agents

• Adalimumab-adaz, adbm, afzb, atto, or bwwd and Infliximab-abda, axxq, dyyb, or qbtx are effective in the treatment of CD patients with moderate to severe disease and can be used for de novo induction and maintenance therapy

Risankizumab   

• An anti-IL-23 monoclonal antibody indicated for the treatment of moderately to severely active CD 
• Phase 3 clinical trials in the induction period (ADVANCE and MOTIVATE) and maintenance period (FORTIFY) support the efficacy and safety of Risankizumab in patients with moderately to severely active CD

Ustekinumab

• An anti-IL-12/23, it is the preferred biologic agent recommended for patients with moderately to severely active CD who are intolerant or have contraindications to conventional therapy or who have failed previous treatment with corticosteroids, thiopurines, Methotrexate, or anti-TNF agents, or in patients without prior exposure to anti-TNF agents
• Should be given as a planned course of treatment until treatment failure, including the need for surgery, or until 12 months after treatment initiation, whichever is shorter

• 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)
  • Antibiotics combined with biologic agents are preferred over a biologic agent alone for inducing fistula remission in outpatients with CD and active perianal fistula with no perianal abscess

Adalimumab and Certolizumab

• May be effective in the treatment of perianal fistulas in CD
• Adalimumab may be used for both induction and maintenance of remission in complex perianal fistulas in CD

Azathioprine or Mercaptopurine

• May be effective for simple perianal fistulae or enterocutaneous fistulae when distal obstruction and abscess have been ruled out
• As monotherapy or in combination with anti-TNF agents, may be used in the initial treatment of rectovaginal fistulas

Infliximab

• Has shown effectivity and may be considered in the treatment and maintenance of remission of complex perianal fistulas, and may be effective in the treatment of enterocutaneous and rectovaginal fistulas in CD
• May be a treatment option for patients with fistulizing CD and unresponsive to conventional therapy (antibiotics, immunosuppressants and drainage), or intolerant or have contraindications to conventional therapy
• Combination with antibiotics is more effective in the treatment of perianal fistulas than Infliximab alone
• Efficacy is increased with seton placement and should be considered in perianal fistula treatment
• Should be given as a planned course of treatment until treatment failure, including the need for surgery or until 12 months

Metronidazole

• May be considered 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

Tacrolimus

• Recommended for treatment of fistulizing CD
• May be considered for short-term treatment of perianal and cutaneous fistulas in CD

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

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

TNF Inhibitors

• May be given to treat severely active CD
• May be an option for patients who do not respond to parenteral corticosteroids
• Infliximab may be given to treat fulminant CD

• 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

• Oral Mesalazine is not recommended for long-term treatment as it has not shown effectivity for maintenance of medically-induced remission in CD patients
• Mesalazine may be an option in preventing postoperative recurrence in patients with isolated ileal resection but has limited benefit

Sulfasalazine and Olsalazine

• There are not enough data showing the effectivity in the maintenance of medically-induced remission of CD patients and are not recommended for long-term treatment

Antibiotics

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

Corticosteroids

• Ineffective for maintenance in CD patients with medically induced remission and should not be used for long-term treatment

Budesonide

• May be effective for short-term maintenance of remission in patients with mild to moderate ileal and/or right colonic disease
• Should not be used beyond 4 months to maintain remission

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)
  • With steroid-dependent CD (administered parenterally) 
• 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

Thiopurines

• Eg Azathioprine, Mercaptopurine
• May be considered 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 corticosteroid courses within 12 months
  • Relapses within 6 weeks of corticosteroid withdrawal
• May be used as monotherapy for patients previously given conventional corticosteroids, 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

TNF Inhibitors 

• Considered in patients with poor prognostic factors or severe disease course
• Recommended in the maintenance of anti-TNF-induced remission
• Combination therapy with anti-TNF agents and thiopurines or Methotrexate may be considered in maintaining anti-TNF-induced remission to avoid development of immunogenicity and loss of response
  • Shown to improve short-term efficacy compared with monotherapy
• Continuation of anti-TNF therapy should be individualized and risks and benefits considered as evidence is insufficient to recommend continuing or withdrawing anti-TNF therapy in CD patients who have achieved long-term remission 
• 1st-line prophylactic treatment in patients at high risk for postoperative recurrence or in patients who have tried and are unresponsive or intolerant of thiopurines
  • Most effective treatment to prevent postoperative recurrence and is recommended to be started within 4 weeks of surgery in high-risk patients

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

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 (corticosteroids, thiopurines, Methotrexate)
• 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

Other Immunosuppressants

• Certolizumab, Natalizumab, Risankizumab, Ustekinumab and Vedolizumab are effective for maintaining remissions
  • Natalizumab may be used for maintenance of Natalizumab-induced remission provided that serum antibody to John Cunningham (JC) virus is negative; testing for anti-JC virus must be done every 6 months and treatment must be discontinued when positive
    • Should not be used in combination with other immunosuppressants due to increased risk of progressive multifocal leukoencephalopathy (PML)
  • Risankizumab is recommended for maintenance of Risankizumab-induced remission
  • Ustekinumab is recommended for maintenance of Ustekinumab-induced remission
  • Vedolizumab is recommended for maintenance of Vedolizumab-induced remission
    • May be used as monotherapy or in combination with thiopurines or Methotrexate to avoid development of immunogenicity and loss of response