Lecture 2: Inflammatory Bowel Disease

• Sulfasalazine

• Olsalazine

• Balsalazide

• Mesalamine

5-Aminosalicylates (5-ASA)

•5-Aminosalicylates (5-ASA)

•Corticosteroids

•Immunosuppressives

• Janus kinase inhibitors

• S1P receptor modulator

• Biologics

Drug categories used to treat IBD

-Infliximab

-Adalimumab

-Golimumab

-Certolizumab

Anti-TNF biologics

-Vedolizumab

-Natalizumab

Anti-integrins (CAM inhibitors)

Ustekinumab

Interleukin (IL)-12/23 antagonist

Risankizumab

Interleukin-23 (IL-23) inhibitor

Tofacitinib

Janus kinase inhibitors

Ozanimod

S1P receptor modulator

Azathioprine and mercaptopurine

Thiopurines (immunosuppresive)

Mesalamine

formulated 5-aminosalicylic acid (5-ASA)

5-Aminosalicylates (5-ASA)

• Thought to work topically

-Activates the production of IL-1, TNF-alpha, and PPARy

-Inhibits lipoxygenase pathway and NFκ β

Mesalamine

-coated in a pH sensitive coating that dissolves at pH 6-7 to release in small intestine and colon

-suppository form is suspended in a wax matrix

-enema form

- Asacol, Apriso, Lialda, Delzicol, and Pentasa

Which ever formulation is relased at the location that is inflamed in the GI tract

How do you pick with 5-ASA to use?

5- Aminosalicylates (5-ASA)

• 1st line - induce/maintain remission in mild-moderate UC

• Not recommended for CD due to lack of efficacy but still widely used

5- Aminosalicylates (5-ASA)

Contraindications

• Hypersensitivity to salicylates (e.g., aspirin)

• Adolescent recovering from viral infection (↑ Reye's syndrome risk)

• Hypersensitivity to sulfonamides (sulfasalazine only)

AEs:

-headache

-dyspepsia

-skin rash

-rarely nephrotoxicity

Sulfasalazine (5-ASA)

AEs:

-headache, nausea, fatigue

-rash, fever, Stevens-Johnson syndrome , pneumonitis, hemolytic

anemia, myelosuppression

• Inhibits intestinal folate absorption- administer with folate

• Oligospermia (reversible)

Glucocorticoids (GCs)

• Anti-inflammatory & immunosuppressive actions

-decreases production and expression of: TNFα, IL-1, IL-8, inflammatory cell adhesion molecules, Phospholipase A2, Cyclooxygenase, and NF-kB

Glucocorticoids (GCs)

-bind to receptors and release Hsp90

-actiavted GCR binds to GREs on gene that result in expression of proteins that suppress immune response, inflammation

Prednisone

• Most common GC used for induction of remission in CD

• Converted to active moiety after 1st pass metabolism

• Intermediate duration of action → Qday dosing

• Most patients respond within 10-14 days and dose can be tapered

Methylprednisolone

which is preferred?

Methylprednisolone or hydrocortisone

Budesonide

-synthetic corticosteroid

-oral once daily, rectal, enema, and suppository forms

• Greater affinity (15x) for GC receptor

-low systemic bioavailability

-

Glucocorticoids (GCs)

-used to induce remission of IBD but not to maintain remission

-avoid long term use

• PO for moderate-severe active IBD

• Admin IV if severely ill

Budesonide

__________________________ PO controlled release useful in:

• Mild-moderate CD of ileum and proximal colon (Entocort®)

• Mild-moderate UC (Uceris®)

Oral Glucocroticoids (GCs)

Short-term systemic side effects

• insomnia, weight gain, emotional lability, GI upset, ↑ blood pressure and blood glucose

Long-term systemic use side effects

• cataracts, hypothalamic-pituitary-adrenal (HPA) axis suppression, Cushing's, immunosuppression, osteoporosis, delayed growth in children, acne

• Azathioprine

• Mercaptopurine

Purine Analogs (immunosuppressives)

Purine Analogs

• Impairs purine biosynthesis and inhibit cellular proliferation of immune cell

• These are prodrugs that are metabolized to their active form:

Purine Analogs

Use -maintain remission (UC, CD)

• Mod-Severe IBD

• Steroid resistant / steroid dependent

• Used as an adjunct to glucocorticoids & biologics

• Treatment with TNFα inhibitors and Aza along with surgery is used for treatment of fistulizing Crohn's

Purine Analogs

• Delayed onset - 17 wks (average)

• ~50% achieve remission in 3-6 months; maintain remission in 80%

-monitor TPMT enzyme activity

-avoid in breast feedin

Purine Analogs

Adverse effects:

• GI upset (severe n/v/d)

• Bone marrow suppression leads to - ↓CBC count

• Hepatotoxicity

-increases risk of lymphoma, hematologic toxicities, and mutagenic potential

DIs:

-allopurinol, febuxostat, mesalamine, ACEis, Trimethoprim/sulfamethoxazole, Warfarin

Folic Acid Analog

(Methotrexate)

-immunosuppressive & anti-inflammatory

-Irreversibly inhibits dihydrofolate reductase

• ↓ thymidine & purine producon = interferes w/ DNA synthesis/repair

• May ↓ IL-1 & ↑ adenosine

• IM weekly

Folic Acid Analog

(Methotrexate)

• Use - Maintenance of CD remission

• off label as alternative to thiopurine to withdraw corticosteroid

• Delayed onset ~ 12 weeks

CIs:

• Pregnancy/breastfeeding

• Alcoholism

• Chronic liver disease

• HIV/AIDS

• Preexisting blood dyscrasias

Folic Acid Analog

(Methotrexate)

Adverse effects

• Bone marrow, liver, lung, skin, and kidney toxicities (monitor)

• Fetal death, congenital anomalies

• Folate (Vit B9) deficiency

• Supplement with folic acid or folinic acid

DIs:

• Live vaccines (↑ risk of infection)

• NSAIDs

TNFα Inhibitors

-immunosuppressive & anti-inflammatory

• Delayed onset - ~2 weeks

Use -induce/maintain remission

• G.I.A for UC

• C.I.A for CD

TNFα Inhibitors

Adverse effects:

• Infusion/injection reactions

• Serious infection

• Reactivation of TB

• Antibodies to the antibody

• Delayed serum-sickness-like reaction

CAM Inhibitors (aka Anti-integrins)

-Monoclonal antibody that binds to and inhibits the α4-integrin subunit.

-they block binding of α4β1 and α4β7 on lymphocytes to MADCAM 1 and prevent lymphocyte recruitment to the intestinal mucosa

Vedolizumab

-binds to α4ß7 integrins found on T-lymphocytes

-use: induction/maintenance of moderate-severe CD or UC

CAM Inhibitors (aka Anti-integrins)

• Admin IV over 30-60 min; DC if no response after 12-14 wks

-can be considered if failure to respond to corticosteroids or are intolerant TNFα inhibitor

CAM Inhibitors (aka Anti-integrins)

Contraindication:

- History of or active PML (natalizumab)

Adverse effects: -headaches, arthralgia, fatigue, infusion reactions , antibodies to the antibody, infection

Natalizumab (CAM inhibitor)

AE: Progressive multifocal leukoencephalopathy (PML) (rare)

• Factors that increase risk:

• Use > 24 months

• History of John Cunningham virus (JCV) infection

• Prior use of immunosuppressive therapies

Natalizumab (CAM inhibitor)

additionally requires enrollment in CD Touch Prescribing Program, s/sx of PML, JC virus

antibody before & Q6 months

IL-12/23 Antagonist (Ustekinumab)

-Fully humanized IgG1K antibody that binds to the p40 protein subunit found in IL-12 and IL-23

-prevents activation of IL-12Rβ1 receptor on quiescent NK and T cells

-inhibits IL-12 and IL-23-mediated inflammatory response

IL-12/23 Antagonist (Ustekinumab)

Uses: induction/maintenance of moderate-severe UC & CD

• Reserved for those with severe disease that failed traditional therapy

IL-12/23 Antagonist (Ustekinumab)

Adverse effects:

•vomiting , nasopharyngitis

- nausea, injection-site erythema, antibody development, infections, TB, skin cancers, Posterior Reversible Encephalopathy Syndrome (PRES)

IL-23 Antagonist (Risankizumab)

-Fully humanized IgG1 monoclonal antibody that binds to the p19 protein subunit of IL-23cytokine

-inhibits the interaction with the IL-23 receptor

Uses: moderate to severe active CD induction/maintenance

IL-23 Antagonist (Risankizumab)

Adverse effects:

• upper respiratory infections, headache, and arthralgia

•hepatotoxicity, infections, TB, anaphylaxis, arthralgia, injection site reactions, abdominal pain, anemia, pyrexia, back pain, arthropathy, and urinary tract infection

Janus kinase(JAK) inhibitor

(Tofacitinib)

Mechanism

• Nonselective inhibitor of JAK, a tyrosine kinase, responsible signal transduction of multiple cytokines involved in the inflammatory cascade

Janus kinase(JAK) inhibitor

(Tofacitinib)

• Use: induction/maintenance of moderate to severe active UC

Adverse effects

• Serious inf ---> hospitalization / death. Includes TB and bacterial, invasive fungal, viral (Herpes zoster)

• Lymphoma/other malignancies

• Thrombosis (DVT, PE, arterial thrombosis)

• Mortality

S1P Receptor Modulator (Ozanimod)

-inhibits which inhibits lymphocyte egress from lymph nodes and subsequent migration to the intestinal tract

-Used for moderate to severe UC

S1P Receptor Modulator (Ozanimod)

Contraindications:

In the past 6 months:

• MI, unstable angina, stroke, transient ischemic attack (TIA) , decompensated heart failure requiring

hospitalization, or class III or IV heart failure

• Presence of Mobitz type II second-degree or third degree atrioventricular (AV) block, sick sinus syndrome, or sino-atrial block without functioning pacemaker

• Severe untreated sleep apnea

• Current use of monoamine oxidase inhibitor

S1P Receptor Modulator (Ozanimod)

AEs:

• ↑ LFT, infecons, bradyarrhythmia, respiratory effects, macular edema, immunosuppression, hyper-/hypotension, headache, posterior reversable posterior leukoencephalopathy (rare)

Females of childbearing age: use contraception during use + 3 months after discontinuation to prevent fetal harm

Antibiotics

Consider for:

• Fistulization or perianal fissuring (complications of CD)

• Pouchitis (complication of UC w/ ileal pouch)

• Generally, not recommended to induce remission

Probiotics (Lactobacillus, Bifidobacterium infantis)

• MOA: Restore gut flora, anti-inflammatory properties.

• May aid in remission induction in UC

• Insufficient evidence in CD

• Separate dosing with antibiotics by at least two hours

Fecal transplant from a healthy individual

• This has proven to be an effective therapy for antibiotic-resistant C. difficile infection

• Several clinical trials have assessed the efficacy of fecal transplant in Crohn disease and ulcerative colitis, with varying results

• Proctitis → PR 5-ASA

• Left-sided colitis → PR 5-ASA ± PO 5-ASA

• Extensive colitis → PO 5-ASA

• If intolerant/unresponsive → add PO corticosteroid (budesonide)

Mildly Active UC - Induction of Remission

• Proctitis → PR 5-ASA

• Left-sided or extensive colitis → PO 5-ASA

• Avoid PO corticosteroids

Mildly Active UC - Maintenance of Remission

Moderate → PO corticosteroid (budesonide)

Moderate-severe →

• PO corticosteroid OR

• TNFα-Inhibitor (if infliximab, then add azathioprine) OR

• Vedolizumab OR

• Tofacitinib

Moderate-Severe UC - Induction of Remission

• Corticosteroid-induced remission → purine analog (azathioprine)

• TNFα-Inhibitor-induced remission → TNFα-Inhibitor

• Vedolizumab-induced remission → vedolizumab

• Tofacitinib-induced remission → tofacitinib

Moderate-Severe UC - Maintenance of Remission

• Preferred C. diff treatment = PO vancomycin

• IV corticosteroids to induce remission

• Refractory on day 5 → Add infliximab or cyclosporine

Acute Severe UC - Hospitalized Patient Management

PO corticosteroid ± azathioprine

CD Low-risk pt w/ minimal systemic complications - induce remission

TNFα-I ± azathioprine

CD High-risk pt - induce remission

• Consider anti-integrin agent (vedolizumab or natalizumab)

• Can be continued for maintenance

if CD treatment with TNFα-I fails

TNFα-I + azathioprine

Pt w/ moderate-to-severe symptoms of CD - induce remission

• Consider purine analog, TNFα-I, or methotrexate if maintenance was steroid-induced

• Consider TNFα-I if maintenance was TNFα-I-induced

• Avoid steroids

Maintenance therapy for CD