Moderate to Severe Luminal and Fistulizing Crohn’s Disease

Last updated June 22, 2022

Key Points

Key Points

  • Crohn’s disease (CD) is a chronic inflammatory bowel disease with substantial morbidity when not adequately controlled.
    • Historically, approximately 20% of patients with CD were hospitalized every year, and the risk of surgery within 1 year of diagnosis was 24%, 36% by 5 years, and 47% by 10 years.
    • In recent years, outcomes have improved, likely because of earlier diagnosis, increasing use of biologics, escalation or alteration of therapy based on disease severity, and endoscopic management of colorectal cancer.
  • The International Organization for the Study of Inflammatory Bowel Diseases characterizes severe disease as having a high risk for adverse disease-related complications, including surgery, hospitalization, and disability, based on a combination of structural damage, inflammatory burden, and impact of quality of life.
    • Contributors to severe disease include large or deep mucosal lesions on endoscopy or imaging, presence of fistula and/or perianal abscess, presence of strictures, prior intestinal resections, particularly of segments >40 cm, presence of a stoma, extensive disease (ileal involvement >40 cm, or pancolitis), anemia, elevated C-reactive protein, and low albumin.
    • With respect to symptoms, patients with severe disease may have at least 10 loose stools per day, daily abdominal pain, presence of anorectal symptoms (eg, anorectal pain, bowel urgency, incontinence, discharge, and tenesmus), systemic corticosteroid use within the prior year, lack of symptomatic improvement despite prior exposure to biologics and/or immunosuppressive agents, or significant impact of the disease on activities of daily living.
  • The Crohn’s Disease Activity Index standardized disease assessment score categorizes severity of disease as: remission <150, mild to moderate as 150–220, moderate to severe as 220–450 and severe >450.
    • For this guideline, moderate to severe disease was considered a Crohn’s Disease Activity Index score of 220 or higher.
  • There are a number of different drug classes available for the management of moderate to severe CD, including:
    • Tumor necrosis factor (TNF)–α antagonists (ie, infliximab, adalimumab, certolizumab pegol), anti-integrin agents (natalizumab, vedolizumab), interleukin 12/23 antagonist (ustekinumab), immunomodulators (thiopurines, methotrexate), and corticosteroids (prednisone, budesonide).
  • In general, most drugs, with the exception of corticosteroids, that are initiated for induction of remission are continued as maintenance therapy.

Treatment

Treatment

1A. In adult outpatients with moderate to severe CD, the AGA recommends the use of anti-TNFα over no treatment for induction and maintenance of remission.

( Moderate , Strong )

Comment: Although the evidence supporting infliximab and adalimumab was moderate certainty, the evidence for certolizumab pegol was low certainty.

612

1B. In adult outpatients with moderate to severe CD, the AGA suggests the use of vedolizumab over no treatment.

  • for the induction and
( Low , Conditional (weak) )
612
  • maintenance of remission.
( Moderate , Conditional (weak) )
612

1C. In adult outpatients with moderate to severe CD, the AGA recommends the use of ustekinumab over no treatment for the induction and maintenance of remission.

( Moderate , Strong )
612

1D. In adult outpatients with moderate to severe CD, the AGA suggests against the use of natalizumab over no treatment for the induction and maintenance of remission.

( Moderate , Conditional (weak) )

Comment: Given evidence of harm in post marketing data from progressive multifocal leukoencephalopathy (PML) and the availability of other drugs, the AGA suggests against the use of natalizumab. Patients who are John Cunningham virus antibody–negative who put a high value on the potential benefits and lower value on PML risk and who will adhere to ongoing monitoring for John Cunningham virus positivity, may consider using natalizumab.

612

2A. In adult outpatients with moderate to severe CD who are naïve to biologic drugs, the AGA recommends the use of infliximab, adalimumab, or ustekinumab over certolizumab pegol for the induction of remission and suggests the use of vedolizumab over certolizumab pegol for the induction of remission.

(, )
(Moderate Low / Strong Conditional)
612

2B. In adult outpatients with moderate to severe CD who never responded to anti-TNFα (primary nonresponse), the AGA recommends the use of ustekinumab and suggests the use of vedolizumab over no treatment for the induction of remission. (, )
(Moderate Low / Strong Conditional)
612

2C. In adult outpatients with moderate to severe CD who previously responded to infliximab (secondary nonresponse), the AGA recommends the use of adalimumab or ustekinumab and suggests the use of vedolizumab over no treatment for the induction of remission.

(, )

Comment: If adalimumab was the first-line drug used there is indirect evidence to suggest the option of using infliximab as a second-line agent.

(Moderate Low / Strong Conditional)
612

3A. In adult outpatients with moderate to severe CD, the AGA suggests against the use of thiopurines over no treatment for achieving remission.

( Very Low , Conditional (weak) )
612

3B. In adult outpatients with quiescent moderate to severe CD (or patients in corticosteroid-induced remission), the AGA suggests the use of thiopurines over no treatment for the maintenance of remission.

( Low , Conditional (weak) )
612

3C. In adult outpatients with moderate to severe CD, the AGA suggests the use of subcutaneous or intramuscular methotrexate monotherapy over no treatment for the induction and maintenance of remission.

( Moderate , Conditional (weak) )
612

3D. In adult outpatients with moderate to severe CD, the AGA suggests against the use of oral methotrexate monotherapy over no treatment for the induction and maintenance of remission.

( Very Low , Conditional (weak) )
612

4. In adult outpatients with moderate to severe CD, the AGA recommends the use of biologic drug monotherapy over thiopurine monotherapy for the induction of remission.

( Moderate , Strong )
612

5A. In adult outpatients with moderate to severe CD who are naïve to biologics and immunomodulators, the AGA suggests the use of infliximab in combination with thiopurines for the induction and maintenance of remission over infliximab monotherapy.

( Moderate , Conditional (weak) )

Comment: Based on indirect evidence, combination infliximab with methotrexate may be more effective over infliximab monotherapy.

612

5B. In adult outpatients with moderate to severe CD who are naïve to biologics and immunomodulators, the AGA suggests the use of adalimumab in combination with thiopurines for the induction and maintenance of remission over adalimumab monotherapy.

( Very Low , Conditional (weak) )

Comment: Based on indirect evidence, combination adalimumab with methotrexate may be more effective over adalimumab monotherapy.

612

5C. In adult outpatients with moderate to severe CD, the AGA makes no recommendation regarding the use of, ustekinumab or vedolizumab in combination with thiopurines or methotrexate over biologic drug monotherapy for the induction and maintenance of remission.

( Evidence Gap , No recommendation )
612

6. In adult outpatients with quiescent CD on combination therapy, the AGA makes no recommendation for withdrawal of either the immunomodulator or the biologic over ongoing combination therapy of a biologic and an immunomodulator.

( Evidence Gap , No recommendation )
612

7. In adult outpatients with moderate to severe CD, the AGA suggests early introduction with a biologic with or without an immunomodulator rather than delaying their use until after failure of 5-aminosalicylates and/or corticosteroids.

( Low , Conditional (weak) )
612

8A. In adult outpatients with moderate to severe CD, the AGA suggests the use of corticosteroids over no treatment for induction of remission.

( Moderate , Conditional (weak) )
612

8B. In adult outpatients with moderate to severe CD, the AGA recommends against the use of corticosteroids over no treatment for maintenance of remission.

( Moderate , Strong )
612

9. In adult outpatients with moderate to severe CD, the AGA recommends against the use of 5-aminosalicylates or sulfasalazine over no treatment for the induction or maintenance of remission.

( Moderate , Strong )
612

10A. In adult outpatients with CD and active perianal fistula, the AGA recommends the use of infliximab over no treatment for the induction and maintenance of fistula remission.

( Moderate , Strong )
612

10B. In adult outpatients with CD and active perianal fistula, the AGA suggests the use of adalimumab, ustekinumab, or vedolizumab over no treatment for the induction or maintenance of fistula remission.

( Low , Conditional (weak) )

Comment: Evidence suggests certolizumab pegol may not be effective for induction of fistula remission.

612

10C. In adult outpatients with CD and active perianal fistula without perianal abscess, the AGA suggests against the use of antibiotics alone over no treatment for the induction of fistula remission.

( Low , Conditional (weak) )
612

11. In adult outpatients with CD and active perianal fistula without perianal abscess, the AGA recommends the use of biologic agents in combination with an antibiotic over a biologic drug alone for the induction of fistula remission.

( Moderate , Strong )
612

a Please see the technical review for the supporting evidence [ https://www.gastrojournal.org/article/S0016-5085(21)00646-6/fulltext ]

Figure 1. Medical Management of Adult Outpatients with Moderate to Severe Luminal Crohn's Disease

Figure 1. Medical Management of Adult Outpatients with Moderate to Severe Luminal Crohn's Disease

Figure 2. Medical Management of Adult Outpatients With Moderate to Severe Fistulizing Crohn's Disease

Figure 2. Medical Management of Adult Outpatients With Moderate to Severe Fistulizing Crohn's Disease

Figure 3. Therapeutic Drug Targets

Figure 3. Therapeutic Drug Targets

Drug Therapy for the Management of Moderate to Severe CD

Drug Therapy for the Management of Moderate to Severe CD

Table 1. Drug Therapy for the Management of Moderate to Severe CD

Table 1. Drug Therapy for the Management of Moderate to Severe CD

Drug Infliximab
Induction
Maintenance
Biologic-naïve induction ✓*
Biologic-naïve maintenance
Primary non-reponder to anti-TNF
Secondary non-responders to infliximab
Perianal fistulizing Crohn's disease: induction
Perianal fistulizing Crohn's disease: maintenance
Drug Adalimumab
Induction
Maintenance
Biologic-naïve induction ✓*
Biologic-naïve maintenance
Primary non-reponder to anti-TNF
Secondary non-responders to infliximab
Perianal fistulizing Crohn's disease: induction
Perianal fistulizing Crohn's disease: maintenance
Drug Certolizumab pegol
Induction
Maintenance
Biologic-naïve induction
Biologic-naïve maintenance
Primary non-reponder to anti-TNF
Secondary non-responders to infliximab
Perianal fistulizing Crohn's disease: induction
Perianal fistulizing Crohn's disease: maintenance
Drug Adalimumab + thiopurine vs adalimumab monotherapy
Induction
Maintenance
Biologic-naïve induction
Biologic-naïve maintenance
Primary non-reponder to anti-TNF
Secondary non-responders to infliximab
Perianal fistulizing Crohn's disease: induction
Perianal fistulizing Crohn's disease: maintenance
Drug Infliximab + thiopurine vs infliximab monotherapy
Induction
Maintenance
Biologic-naïve induction
Biologic-naïve maintenance
Primary non-reponder to anti-TNF
Secondary non-responders to infliximab
Perianal fistulizing Crohn's disease: induction
Perianal fistulizing Crohn's disease: maintenance
Drug Natalizumab
Induction ×
Maintenance ×
Biologic-naïve induction
Biologic-naïve maintenance
Primary non-reponder to anti-TNF
Secondary non-responders to infliximab
Perianal fistulizing Crohn's disease: induction
Perianal fistulizing Crohn's disease: maintenance
Drug Ustekinumab
Induction
Maintenance
Biologic-naïve induction ✓*
Biologic-naïve maintenance
Primary non-reponder to anti-TNF
Secondary non-responders to infliximab
Perianal fistulizing Crohn's disease: induction
Perianal fistulizing Crohn's disease: maintenance
Drug Vedolizumab
Induction
Maintenance
Biologic-naïve induction ✓*
Biologic-naïve maintenance
Primary non-reponder to anti-TNF
Secondary non-responders to infliximab
Perianal fistulizing Crohn's disease: induction
Perianal fistulizing Crohn's disease: maintenance
Drug Oral methotrexate monotherapy
Induction ×
Maintenance ×
Biologic-naïve induction
Biologic-naïve maintenance
Primary non-reponder to anti-TNF
Secondary non-responders to infliximab
Perianal fistulizing Crohn's disease: induction
Perianal fistulizing Crohn's disease: maintenance
Drug Subcutaneous or intramuscular methotrexate monotherapy
Induction
Maintenance
Biologic-naïve induction
Biologic-naïve maintenance
Primary non-reponder to anti-TNF
Secondary non-responders to infliximab
Perianal fistulizing Crohn's disease: induction
Perianal fistulizing Crohn's disease: maintenance
Drug Thiopurine monotherapy
Induction ×
Maintenance
Biologic-naïve induction
Biologic-naïve maintenance
Primary non-reponder to anti-TNF
Secondary non-responders to infliximab
Perianal fistulizing Crohn's disease: induction
Perianal fistulizing Crohn's disease: maintenance
Drug Corticosteroids
Induction
Maintenance ×
Biologic-naïve induction
Biologic-naïve maintenance
Primary non-reponder to anti-TNF
Secondary non-responders to infliximab
Perianal fistulizing Crohn's disease: induction
Perianal fistulizing Crohn's disease: maintenance
Drug 5-aminosalicylate/sulfasalazine
Induction ×
Maintenance ×
Biologic-naïve induction
Biologic-naïve maintenance
Primary non-reponder to anti-TNF
Secondary non-responders to infliximab
Perianal fistulizing Crohn's disease: induction
Perianal fistulizing Crohn's disease: maintenance
Drug Antiobiotic monotherapy
Induction
Maintenance
Biologic-naïve induction
Biologic-naïve maintenance
Primary non-reponder to anti-TNF
Secondary non-responders to infliximab
Perianal fistulizing Crohn's disease: induction ×
Perianal fistulizing Crohn's disease: maintenance
Drug Biologic monotherapy vs thiopurine monotherapy
Induction
Maintenance
Biologic-naïve induction
Biologic-naïve maintenance
Primary non-reponder to anti-TNF
Secondary non-responders to infliximab
Perianal fistulizing Crohn's disease: induction
Perianal fistulizing Crohn's disease: maintenance
Drug Biologic agents in combination with antibiotics vs biologic monotherapy
Induction
Maintenance
Biologic-naïve induction
Biologic-naïve maintenance
Primary non-reponder to anti-TNF
Secondary non-responders to infliximab
Perianal fistulizing Crohn's disease: induction
Perianal fistulizing Crohn's disease: maintenance
* Over certolizumab pegol.
✓ = strong recommendation for; ✓ = conditional recommendation for;
× = conditional recommendation against; × = strong recommendation against

Recommendation Grading

Source Citation

Feuerstein JD, Ho EY, Shmidt E, Singh H, Falck-Ytter Y, Sultan S, Terdiman JP; American Gastroenterological Association Institute Clinical Guidelines Committee. AGA Clinical Practice Guidelines on the Medical Management of Moderate to Severe Luminal and Perianal Fistulizing Crohn's Disease. Gastroenterology. 2021 Jun;160(7):2496-2508. doi: 10.1053/j.gastro.2021.04.022. PMID: 34051983.

Disclaimer

This resource is for informational purposes only, intended as a quick-reference tool based on the cited source guideline(s), and should not be used as a substitute for the independent professional judgment of healthcare providers. Practice guidelines are unable to account for every individual variation among patients or take the place of clinician judgment, and the ultimate decision concerning the propriety of any course of conduct must be made by healthcare providers after consideration of each individual patient situation. Guideline Central does not endorse any specific guideline(s) or guideline recommendations and has not independently verified the accuracy hereof. Any use of this resource or any other Guideline Central resources is strictly voluntary.

Codes

CPT Codes

Code Descriptor
44361 Small intestinal endoscopy
44360 Small intestinal endoscopy
45378 Colonoscopy
45380 Colonoscopy

ICD-10 Codes

Code Descriptor Documentation Concepts Quality/Performance
K91.2 Postsurgical malabsorption, not elsewhere classified RXHCC66
K50.911 Crohn's disease, unspecified, with rectal bleeding Site Complications Manifestations HCC35, RXHCC67
K60.3 Anal fistula
K90.49 Malabsorption due to intolerance, not elsewhere classified
K50.80 Crohn's disease of both small and large intestine without complications Site Complications Manifestations HCC35, RXHCC67
K63.0 Abscess of intestine
K50.90 Crohn's disease, unspecified, without complications Site Complications Manifestations HCC35, RXHCC67
K60.4 Rectal fistula