IBD

It is chronic inflammation of the gastrointestinal (GI) tract

Pathophysiology and Etiology

Pathophysiology

• Severity varies - asymptomatic remission to mild and manageable to severe where surgeries are needed 

• Two hypothesis:

  • Primary dysregulation of the mucosal immune system resulting in excessive immunologic responses to normal microflora

  • Changes in the composition of the gut microflora and/or deranged epithelial barriers function that causes pathologic responses (inflammation) from the normal mucosal immune system 

• Etiology poorly understood, but potential factors include

  • Genetics (first degree relatives have a 4- to 20-fold greater risk), predisposing immunological factors, infection, emotional stress, environment (eg. diet, smoking, etc)

• Chronic inflammation of the GI tract leading to diarrhea 

  • Exact cause of inflammation is unknown 

  • Inflammation is considered secondary to an antigen driven response 

Etiology 

UC vs Crohns

Ulcerative Colitis

• Location 

  • Colon, rectum

  • Backwash ileitis = rare involvement of the terminal ileum

• Mucosal penetration 

  • Superficial

• Distribution 

  • Continuous 

Crohn’s Disease 

• Location

  • Anywhere from mouth to anus

  • Terminal ileum (most common)

• Mucosal penetration

  • Deep transmural lesions; affecting mucosa, submucosa, muscle, and serosa

• Distribution 

  • Discontinuous

  • Patchy “cobblestone” appearance

Signs and symptoms

• Diarrhea and frequent bowel movements

• Abdominal pain

• Fatigue

• Fever

• Weight loss 

Complications

UC complications

• Hemorrhoids

• Anal fissures

• Perirectal abscess

• Toxic megacolon 

  • colonic distension of > 6 cm plus acute colitis and systemic toxicity (fever, tachycardia, elevated WBC)

CD complication 

• Structure

• Abscess

• Fistula

• Nutritional deficiencies 

UC Mild treatment

Uc Moderate-Severe Induction

UC Moderate-Severe: Induction 

• Any option on the previous slide can work (all are strong recommendations) 

• Highest quality of evidence for: infliximab and JAK inhibitors 

• Systemic steroids are not ideal for induction as a different medication will need to be used for maintenance 

  • Can still use steroids in combination with other medications

UC Moderate-Severe: Maintenance

UC Moderate-Severe: Maintenance 

• If used for induction, use it for maintenance 

  • The only caveat is systemic steroids; do not use for maintenance 

• If using a systemic steroid or immunomodulator, goal is to try to taper down over time

  • Steroid over a few weeks, immunomodulator over months

UC Hospitalization and Example Regimen

CD Mild Treatment

CD Moderate-Severe: Induction

CD Moderate-Severe: Induction 

• Start with more advanced therapy first (top-down)

  • TNFs, Vedolizumab, ustekinumab, risankizumab

    • Upadacitinib only for patients who failed TNF treatments

    • Systemic steroids monotherapy can be used are not preferred

    • Can add systemic steroids to these regimens

• Infliximab + azathioprine is better than infliximab monotherapy 

• Azathioprine and methotrexate are not recommended for induction monotherapy

CD Moderate-Severe Maintenance

CD Moderate-Severe: maintenance 

• If used for induction, use it for maintenance

  • The only caveat is systemic steroids; do not use for maintenance 

• If using a systemic steroid or immunomodulator, goal is to try to taper down over time 

  • Steroid over a few weeks, immunomodulator over months

CD hospitalization

Immunomodulator: Mesalamine/5-ASA

• Dose: 1-4 g daily 

  • Route (suppository, enema, oral) based on location of disease 

• Labs/screening: CMP, CBC, LFTs

• SE:

  • Nausea, vomiting headache

  • Delayed hypersensitivity reaction

  • Nephrotoxicity (rare

• Pearls

  • Intolerance syndrome (diarrhea, fever, abdominal pain); often mistaken as exacerbation of UC

  • Active component of sulfasalazine

    • Used instead of sulfasalazine due to lower risk of adverse effects

Corticosteroid: Budesonide 

• Dose: 9 mg once daily 

• Pears:

  • Use extended released or delayed release - limit systemic absorption

Antimetabolite: Methotrexate (Trexall)

• Dose:

  • 7.5-15 mg once weekly (PO, subq, IM)

  • Increase by 2.5-5 mg every 4-12 week

  • Usually range 7.5-20 mg once weekly

  • Given with folic acid 1-5 mg daily 

• Labs: SCr, CBC, LFTs, Tuberculosis screen, Hep B and C screen

• BOXED WARNING: serious adverse effects involving bone marrow, GI tract, liver, lungs, skin, and kidneys

• Other AEs: 

  • N/V, elevated LFTs

  • Increased risk of infections

• Contraindications:

  • Pregnancy (teratogenic)

  • hypersensitivity 

  • Alcohol use disorder

  • Liver disease

  • Immunodeficiency syndromes

  • Anemia

  • Leukopenia

  • Thrombocytopenia 

•  Give with Folic Acid 

• Do not give in pregnancy (teratogenic)

Antimetabolite: Azathioprine

• Dose: 50 mg PO daily, titrated up to 2.5 mg/kg/day

• Labs/screening:

  • TMPT genetic test

  • CBC, CMP, LFTs

  • Renal and hepatic function

  • Regular skin checks

• BOXED WARNING: malignancy 

• SE:

  • N/V (often severe)

  • Diarrhea

  • Alopecia

  • Hematologic toxicities

  • Increased risk of infections

  • Liver dysfunction 

  • Pancreatitis

  • Sun sensitivity 

• Pearls:

  • Interacts with xanthine oxidase inhibitors through inhibition of the breakdown of 6-MP to 6-TU (inactive product) 

  • Increased risk of hematologic toxicity with TPMT or NUDT15 deficiency 

  • Avoid live vaccines 

  • safe in pregnancy 

  • Wear sunscreen (increased risk of skin cancer)

Azathioprine (AZA)/6-mercaptopurine (6-MP) metabolism

• TPMT polymorphism have been shown to influence patient responsiveness to therapy - specifically, TMPT deficiency increases risk for ADE

TNF inhibitors: Adalimumab (Humira), infliximab (Remicade)

• Dose: all subq except infliximab (IV)

• Labs/Screenings: Tuberculosis, Hep B and C, HIV, CBC with diff

• BOXED WARNING: Serious infections and malignancy 

• SE:

  • Risk of infections (UTI, URTI) and malignancies

• Demyelinating disorders

• Rash

• injection/infusion site reaction 

• GI intolerance 

• Worsening heart failure 

• Pearls:

  • Drug neutralizing antibodies can form against them → risk of ineffective treatment over time 

  • Do not use in heart failure NYHA class III/IV

  • Avoid live vaccines

  • CAN use during pregnancy

Biologics: infections and Malignancies

• Results of their powerful immunosuppression and impacts on cell function, biologics increase the risk for infection and malignancies (ie. cancer)

• Many biologics (and other potential immunosuppressors contain BOXED WARNINGS or other warnings associated with this risk 

• Other things to consider: administration of live vaccines, screening for latent infections (TB, HIV, Hep B/C, etc)

IL-23 Inhibitor: Risankizumab (Skyrizi)

• Dose: subq

• Labs/Screening: CBC, LFTs, CMP, Tuberculosis, Hep B and C, and HIV screening  

• ADE:

  • Risk of serious infections (typically URTI)

  • Elevated LFTs

• Pearls:

  • Drug neutralizing antibodies can form against them → risk of ineffective treatment over time

  • Avoid live vaccine 

  • Do not use pregnancy (lack of data)

IL-23 and IL-12 inhibitor: Ustekinumab (Stelara)

• Dose: subq

• Labs/screening: CBC, LFTs, CMP, tuberculosis, Hep B and C, HIv 

• ADE: 

  • risk of serious infection

  • Nasopharyngitis

  • Skin cancer risk 

• Pearls: 

  • Drug neutralizing antibodies can form against them → risk of ineffective treatment over time

  • Avoid in live vaccines

  •  Do not use in pregnancy (lack of data)

Biologics: antidrug antibodies

• Cause some level of immune response against them (AKA immunogenicity)

• As a result of that immunogenicity, our body sometimes produces antibodies against biologics

  • Antidrug antibodies 

• Leads to reduction of failure of response to biologics over time - key reason why patient may need to switch treatments

• Most common anti-cytokine biologics (TND, IL)

JAK inhibitors: Tofacitinib (Xeljanz), upadacitinib (Rinvoq)

• Oral agents

• Labs/Screenings: CBC, LFTs,  Tuberculosis, Hep B and C 

• BOXED WARNING:

  • Infection, malignancies, major adverse CV events, thrombosis, mortality ( in pt with CV risk factors)

    • Discontinue JAK-i in patients with MI or stroke 

• SE:

• Hepatotoxicity 

• Gi perforation 

• Blood cell disorders

• N/V/D, headache 

• Do not initiate therapy in patients with an absolute lymphocyte count <500 cells/mm3, ANC <1000 cells/mm3, or hemoglobin < 9g/dl

• Do not use in combo with other immunosuppressants (csDMARDs and steroid ok)

• Avoid live vaccines

•  Do not use in pregnancy (lack of data)

Integrin Inhibitor: Vedolizumab (Entyvio)

• Dose: IV for induction, followed by either IV or subq maintenance

• Labs: LFTs, Tuberculosis screen 

• SE:

  • Risk of infection 

  • Nasopharyngitis

  • Elevated liver enzyme

  • Infusion-related reactions 

• Pearls:

  • Avoid in vaccines

  • Possibly safe in pregnancy?

S1P receptor Modulator: Ozanimod (Zeposia)

• Dose: PO

• Labs/screening: CBC, CMP, LFTs ophthalmic exam, ECG, HR/BP, varicella zoster serology

• SE:

  • URTI 

  • Varicella zoster infection 

  • AV block, bradycardia 

  • Increased BP 

  • Hepatotoxicity 

  • Lymphopenia 

  • Macular edema 

  • Neurotoxicity and PML 

  • Decreased pulmonary function

• CI: MI, unstable angina, stroke, TIA, HFrEF, heart block, severe untreated sleep apnea, use of MAOI

• Pearls:

  • Avoid live vaccines 

  • Do not use in pregnancy (lack of data)

Sphingosine 1-phosphate (S1P) Receptor Modulators ADE

• S1P receptors affect multiple organ systems which is why they cause eye and CV adverse effects