CROHN'S DISEASE (CD)



























Crohn's disease drugs
Biologicals
  • TNF inhibitors
    • Adalimumab (Humira®)
    • Certolizumab (Cimzia®)
    • Infliximab (Remicade®)

  • IL-12 / IL-23 inhibitor
    • Ustekinumab (Stelara®)

  • IL-23 inhibitor
    • Risankizumab (Skyrizi®)

  • T-cell agents
    • Natalizumab (Tysabri®)
    • Vedolizumab (Entyvio®)
Immunosuppressants
  • Dihydrofolate reductase inhibitors
    • Methotrexate (Trexall®, etc.)

  • Thiopurines
    • Azathioprine (Imuran®)
    • Mercaptopurine (6-MP)

  • Corticosteroids
    • Oral corticosteroids
    • Budesonide capsule (Entocort) - local effect

  • Aminosalicylates
    • Sulfasalazine (Azulfidine®)

  • Reference [15]
ACG 2018 Crohn's Disease Treatment Recommendations
Mild-to-moderate active disease
  • Definition: (CDAI score of 150 - 220) ambulatory and able to tolerate oral alimentation without manifestations of dehydration, systemic toxicity (high fevers, rigors, and prostration), abdominal tenderness, painful mass, intestinal obstruction, or > 10% weight loss. These individuals do not have severe endoscopic lesions.
  • Treatment options
    • Sulfasalazine
    • Budesonide (Entocort®) - can be used for ileocecal disease
  • Not recommended
    • Mesalamine, metronidazole, ciprofloxacin, antimycobacterial therapy
Moderate-to-severe active disease
  • Definition: (CDAI score of 220 - 450) prominent symptoms of fever, significant weight loss, abdominal pain or tenderness, intermittent nausea or vomiting (without obstructive findings), or significant anemia. They typically have moderate to severely active endoscopic mucosal disease.
  • Treatment options
    • Oral or intravenous corticosteroids
    • TNF inhibitors (infliximab, adalimumab, certolizumab pegol)
    • Natalizumab (Tysabri®)
    • Vedolizumab (Entyvio®)
    • Ustekinumab (Stelara®) - patients who have failed previous treatment with corticosteroids, thiopurines, methotrexate, or anti-TNF inhibitors, or who have had no prior exposure to anti-TNF inhibitors
  • Adjunctive or steroid-sparing treatment
    • Azathioprine, 6-MP, or methotrexate - clinical response can take up to 12 weeks so they are not effective for inducing remission. These agents can be used as adjunctive therapy for reducing immunogenicity against biologic therapy (6-mercaptopurine or azathioprine typically at reduced doses and methotrexate 12.5–15 mg orally once weekly)
    • Combination therapy of infliximab with immunomodulators (azathioprine, 6-MP) is more effective than treatment with either immunomodulators alone or infliximab alone in patients who are naive to those agents
  • Not recommended
    • Cyclosporine, tacrolimus, and mycophenolate mofetil
Severe/fulminant active disease
  • Definition: (CDAI score > 450) persistent symptoms despite the introduction of conventional corticosteroids or biologic agents as outpatients, or individuals presenting with high fevers, persistent vomiting, evidence of intestinal obstruction, significant peritoneal signs such as involuntary guarding or rebound tenderness, cachexia, or evidence of an abscess. They have endoscopic or radiographic evidence of severe mucosal disease.
  • Treatment options (severe disease)
    • Intravenous corticosteroids
    • TNF inhibitors (infliximab, adalimumab, certolizumab pegol)
  • Treatment options (fulminant disease)
    • Intravenous corticosteroids
    • Infliximab (Remicade®)
Fistulizing disease
  • Treatment options
    • Infliximab (Remicade®) - is effective
    • Adalimumab and certolizumab pegol - may be effective
    • Azathioprine and 6-MP - may be effective
    • Tacrolimus - may be used
    • Antibiotics (metronidazole) - may be effective for simple perianal fistulas and may improve response to infliximab
Maintenance of remission
  • Definition: (CDAI score < 150) asymptomatic
  • Recommended treatment
    • In general, patients should continue therapy with the drug that was used to induce remission. If corticosteroids were used, patients should be transitioned to azathioprine, 6-MP, or methotrexate
    • Budesonide (Entocort®) should not be used to maintain remission beyond 4 months
  • Not recommended
    • Sulfasalazine, olsalazine

  • Reference [3,14,15]
AGA 2014 Crohn's Disease Treatment Recommendations
Initial therapy
  • Mild disease - no systemic symptoms; CDAI score 150 - 220
    • Ileum and/or proximal colon involvement
      • Budesonide 9 mg once daily ± azathioprine 2 - 3 mg/kg/day; OR
      • ✝Prednisone 40 - 60 mg once daily ± azathioprine 2 - 3 mg/kg/day
    • Diffuse or left colon
      • ✝Prednisone 40 - 60 mg once daily ± azathioprine 2 - 3 mg/kg/day

  • Moderate - severe disease - CDAI score 220 - 450
    • TNF inhibitor ± thiopurine
      • TNF inhibitor - infliximab or adalimumab
      • Thiopurine - azathioprine 2 - 3 mg/kg/day or mercaptopurine 1 - 1.5 mg/kg/day
      • For patients who cannot tolerate a thiopurine, methotrexate 25 mg sub-Q or IM once weekly may be used

  • ✝Prednisone is given until resolution of symptoms which typically occurs within 7 - 28 days. It is then tapered by 5 - 10 mg/week down to 20 mg. From 20 mg, it is tapered by 2.5 - 5 mg/week until stopped.
Maintenance of remission
  • Mild disease - no systemic symptoms; CDAI score 150 - 220
    • Option 1 - stop therapy; this option has a high relapse rate
    • Option 2 - budesonide 6 mg/day; time to relapse is prolonged; remission rates are similar to placebo at 1 year
    • Option 3 (one of the following)
      • Azathioprine 2 - 3 mg/kg/day
      • Mercaptopurine 1 - 1.5 mg/kg/day
      • Methotrexate 25 mg sub-Q or IM once weekly

  • Moderate - severe disease - CDAI score 220 - 450
    • Steroid-induced remission
      • Option 1 - thiopurine or methotrexate
      • Option 2 - TNF inhibitor ± thiopurine
    • TNF inhibitor-induced remission
      • TNF inhibitor ± thiopurine
        • TNF inhibitors - infliximab, adalimumab, or certolizumab pegol
        • Thiopurine - azathioprine 2 - 3 mg/kg/day or mercaptopurine 1 - 1.5 mg/kg/day
        • Methotrexate 25 mg sub-Q or IM once weekly may be used
Refractory disease
  • Natalizumab (Tysabri®) 300 mg IV every 4 weeks
  • Vedolizumab (Entyvio®)
    • Starting: 300 mg IV at Weeks 0, 2, and 6
    • Maintenance: 300 mg IV every 8 weeks
  • Ustekinumab (Stelara®) - initial weight-based IV infusion followed by 90 mg SQ every 8 weeks


  • Reference [16]
Evaluating patients who fail treatment while on TNF inhibitor therapy
Step 1 - Check trough TNF inhibitor levels
  • Target trough levels for TNF inhibitors:
    • Adalimumab (Humira®): ≥ 7.5 mcg/ml
    • Certolizumab Pegol (Cimzia®): ≥ 20 mcg/ml
    • Golimumab (Simponi®): unknown
    • Infliximab (Remicade®): ≥ 5 mcg/ml
Step 2
  • If trough levels are adequate, suspect drug failure and consider switching to another drug class
  • If trough levels are low, check for anti-drug antibodies
  • Low/absent trough with no anti-drug antibodies
    • Possible pharmacokinetic failure
    • Shorten dosing interval, and/or increase dose, and/or add immunosuppressant
  • Absent trough with high-titer anti-drug antibodies
    • Possible immune-mediated failure
    • Change to another TNF inhibitor or use a different class
  • Low trough with low- or high-titer anti-drug antibodies
    • Indeterminate. Consider one of the above approaches.


  • Reference [13]
CDAI SCORE
  • The value for each item is multiplied by its weight
  • The weighted values are then totaled for the CDAI score
Item Weight
Total number of liquid or very soft stools over last 7 days 2
Degree of abdominal pain over last 7 days
  • Scale: 0 - none, 1 - mild, 2 - moderate, 3 - severe
  • Assign a value for each day and sum the values
 5
General well-being over last 7 days
  • Scale: 0 - well, 1 - below normal, 2 - poor, 3 - very poor, 4 - terrible)
  • Assign a value for each day and sum the values
 7
Presence of the following (one point for each):
  • Arthritis/arthralgia
  • Mucocutaneous lesions (e.g. erythema nodosum, aphthous ulcers)
  • Iritis/Uveitis
  • Anal disease (e.g. fistula, fissure, etc.)
  • Fistula (cutaneous, vesicular, vaginal, etc.)
  • Fever (> 100.04°F, 37.8°C) in past week
 20
Use of antidiarrheal in last week (Yes - 1, No - 0) 30
Abdominal mass
  • Scale: 0 - none, 2 - questionable, 5 - definite
 10
Hematocrit (Hct) below normal
  • Males
    • 47 minus current Hct
  • Females
    • 42 minus current Hct
 6
Percent weight loss (Healthy weight - current weight)/Healthy weight X 100 1

  • Reference [3]
CDAI score interpretation
CDAI score Disease activity
< 150 Remission
150 - 220 Mild-moderate disease
220 - 450 Moderate-severe disease
> 450 Severe-fulminant


Ustekinumab vs Placebo in Patients with Crohn's Disease who Failed TNF Inhibitors, NEJM (2012) [PubMed abstract]
  • The study enrolled 526 adults with Crohn's Disease who had failed TNF inhibitor therapy
Main inclusion criteria
  • Crohn’s disease of at least 3 months’ duration
  • Disease confirmed by radiography and/or endoscopy
  • Failed infliximab, adalimumab, or certolizumab pegol
  • Active disease, defined as CDAI score of ≥ 220
Main exclusion criteria
  • Crohn’s complications (e.g. strictures, stenoses, short gut syndrome)
  • Bowel resection, diversion, or placement of a stoma within 6 months
Baseline characteristics
  • Average age - 39 years
  • Average duration of disease - 12 years
  • Average CDAI - 323
  • Receiving corticosteroids at baseline - 50%
Randomized treatment groups
  • Group 1 (131 patients): Ustekinumab 1 mg/kg IV one time
  • Group 2 (132 patients): Ustekinumab 3 mg/kg IV one time
  • Group 3 (131 patients): Ustekinumab 6 mg/kg IV one time
  • Group 4 (132 patients): Placebo
  • Patients were permitted to continue other drug therapies for Crohn's disease
  • After 6 weeks, 145 patients who had a response to ustekinumab underwent a second randomization to receive ustekinumab 90 mg SQ or placebo at weeks 8 and 16
Primary outcome: Clinical response (defined as ≥100-point decrease from the baseline CDAI score) at week 6
Results

Duration: 6 weeks
Outcome Ust 1mg Ust 3mg Ust 6mg Placebo Comparisons
Primary outcome 36.6% 34.1% 39.7% 23.5% 1 vs 4 p=0.02 | 2 vs 4 p=0.06 | 3 vs 4 p=0.005
Remission at 22 weeks (maintenance phase) Ustekinumab - 41.7%, Placebo - 27.4%, (p=0.03)

Findings: Patients with moderate-to-severe Crohn’s disease that was resistant to TNF antagonists had an increased rate of response to induction with ustekinumab, as compared with placebo. Patients with an initial response to ustekinumab had significantly increased rates of response and remission with ustekinumab as maintenance therapy.
GEMINI 2 Study - Vedolizumab vs Placebo for Moderate to Severe Crohn's Disease, NEJM (2013) [PubMed abstract]
  • The GEMINI 2 study enrolled 1093 patients with CD
Main inclusion criteria
  • ≥ 18 years old
  • 3 months of moderate to severe disease (CDAI 220 - 450)
  • No response or unacceptable side effects from steroids, immunosuppressants, or TNF inhibitors
  • One of the following: C-reactive protein > 2.87 mg/L, colonoscopy showing ≥ 3 large ulcers or ≥ 10 aphthous ulcers, Fecal calprotectin > 250 mcg/g + radiological findings of CD
Main exclusion criteria
  • Adalimumab within previous 30 days
  • Infliximab or certolizumab within 60 days
  • History of extensive intestinal surgery
Baseline characteristics
  • Average age 36 years
  • Average CDAI score - 324
  • Treatment with steroids only - 34%
  • Treatment with immunosuppressants only - 16%
  • Treatment with steroids + immunosuppressants - 17%
  • No steroids or immunosuppressants - 33%
  • Prior TNF inhibitor - 62%
Randomized treatment groups:
Induction phase
  • Patients were randomized to one of two groups:
    • Group 1 (148 patients) - Placebo infusion
    • Group 2 (220 patients) - Vedolizumab 300 mg at Weeks 0 and 2
Maintenance phase
  • Patients were randomized to one of three groups:
    • Group 1 (153 patients) - Placebo infusion
    • Group 2 (154 patients) - Vedolizumab 300 mg every 8 weeks
    • Group 3 (154 patients) - Vedolizumab 300 mg every 4 weeks
    • Stable doses of oral prednisone (≤30 mg per day) or budesonide (≤9 mg per day), immunosuppressive agents, mesalamine, and antibiotics were permitted
    • The induction phase also had an open-label vedolizumab arm that included 747 patients
    • Vedolizumab-responders from the induction phase (randomized and open-label) were re-randomized into the maintenance phase
Primary outcome:
  • Induction phase - clinical remission (CDAI score of ≤ 150 points) at week 6
  • Maintenance phase - clinical remission (CDAI score of ≤ 150 points) at week 52
Results

Duration: Induction phase - 6 weeks | Maintenance phase - 52 weeks
Outcome Placebo Ved q8wk Ved q4wk Comparisons
Primary outcome (induction phase) 6.8% 14.5% N/A p=0.02
Primary outcome (maintenance phase) 21.6% 39% 36.4% 1 vs 2: p<0.001 | 1 vs 3: p=0.004
≥ 100-point decrease in CDAI at week 6 25.7% 31.4% N/A p=0.23
  • More serious adverse events occurred in the vedolizumab groups than in the placebo groups (24.4% vs 15.3%)
  • More serious infections occurred in the vedolizumab groups than in the placebo groups (5.5% vs 3%)

Findings: Vedolizumab-treated patients with active Crohn's disease were more likely than patients receiving placebo to have a remission, but not a CDAI-100 response, at week 6; patients with a response to induction therapy who continued to receive vedolizumab (rather than switching to placebo) were more likely to be in remission at week 52. Adverse events were more common with vedolizumab.
ENACT 1 and 2 Studies - Natalizumab vs Placebo for Moderate to Severe Crohn's Disease, NEJM (2005) [PubMed abstract]
  • The ENACT 1 and 2 studies enrolled 905 patients with CD
Main inclusion criteria
  • ≥ 18 years old
  • 6 months of moderate to severe disease (CDAI 220 - 450)
  • Disease confirmed within previous 36 months by endoscopy, surgery, or imaging
Main exclusion criteria
  • TNF inhibitors within previous 3 months
  • Active obstructing stricture, fistula, or abscess
Baseline characteristics
  • Average age 38 years
  • Average CDAI score - 302
  • Treatment with steroids only - 38%
  • Treatment with immunosuppressants only - 33%
  • Treatment with steroids + immunosuppressants - 14%
Randomized treatment groups
  • Group 1 (724 patients) - Natalizumab 300 mg IV every 4 weeks
  • Group 2 (181 patients) - Placebo IV every 4 weeks
  • Immunosuppressants were continued at current doses
  • Steroids were continued until Week 10, at which point, patients were required to attempt tapering
  • ENACT-1 lasted 12 weeks. In ENACT-2, patients from ENACT-1 who had a response were randomized to natalizumab or placebo for an additional 44 weeks.
Primary outcome:
  • ENACT 1 - proportion of patients with response (defined by a decrease in the Crohn’s Disease Activity Index (CDAI) score of at least 70 points) at week 10
  • ENACT 2 - proportion of patients with sustained response through Week 36. Loss of response was defined by an increase in the CDAI score of at least 70 points after Week 12 and by an absolute score of at least 220 or the need for intervention after Week 12.
Results

Duration: ENACT 1 - 10 weeks | ENACT 2 - 36 weeks
Outcome Natalizumab Placebo Comparisons
Primary outcome (ENACT 1) 56% 49% p=0.05
Primary outcome (ENACT 2) 61% 28% p=0<0.001
  • The rates of serious infections were similar between groups in both studies
  • In an open-label extension study, one patient treated with Natalizumab died of PML

Findings: Induction therapy with natalizumab for Crohn's disease resulted in small, nonsignificant improvements in response and remission rates. Patients who had a response had significantly increased rates of sustained response and remission if natalizumab was continued every four weeks. The benefit of natalizumab will need to be weighed against the risk of serious adverse events, including progressive multifocal leukoencephalopathy.
SONIC Study - Infliximab vs Azathioprine vs Both for Moderate-to-Severe Crohn's Disease, NEJM (2010) [PubMed abstract]
  • The SONIC study enrolled 508 patients with moderate-to-severe CD
Main inclusion criteria
  • ≥ 21 years old
  • Moderate-to-severe disease (CDAI 220 - 450)
  • One of the following: corticosteroid-dependent, considered for 2nd course of steroids within 12 months, no response to mesalamine after 4 weeks, no response to budesonide after 4 weeks
Main exclusion criteria
  • Previous treatment with azathioprine, 6MP, methotrexate, or anti-TNF
  • Decreased TPMT activity
  • Abdominal surgery within the previous 6 months
Baseline characteristics
  • Median age 34 years
  • Average CDAI score - 287
  • Median disease duration - 2.3 years
  • Treatment with oral steroids - 27%
  • Receiving budesonide - 14%
  • Receiving 5-Aminosalicylic compounds - 54%
Randomized treatment groups
  • Group 1 (170 patients) - Azathioprine 2.5 mg/kg/day
  • Group 2 (169 patients) - Infliximab 5 mg/kg at Weeks 0, 2, and 6, then every 8 weeks
  • Group 3 (169 patients) - Azathioprine + infliximab
  • Oral mesalamine was continued at a stable dose
  • Steroids (oral and budesonide) could be used up to Week 14, then they had to be tapered
  • Colonoscopy was performed at baseline and Week 26
  • At Week 30, patients were given the option to continue on current treatment while maintaining blinding to Week 50
Primary outcome: Rate of corticosteroid-free clinical remission (CDAI < 150) at week 26
Results

Duration: 26 weeks
Outcome Azathioprine Infliximab Both Comparisons
Primary outcome 30% 44% 57% 1 vs 2, p=0.006 | 1 vs 3, p<0.001 | 2 vs 3, p=0.02
  • This study had a very large dropout rate which lowered its validity on a number of secondary outcomes. Only the primary outcome is presented here.

Findings: Patients with moderate-to-severe Crohn's disease who were treated with infliximab plus azathioprine or infliximab monotherapy were more likely to have a corticosteroid-free clinical remission than those receiving azathioprine monotherapy.