Inflammatory Bowel Disease

extra-intestinal manifestations of UC and CD

(inflammation starts in the GI tract but can then spread throughout the body) - arthritis/arthralgia - hepatobiliary - abnormal LFTs, fatty liver, hepatits, cirrhosis - dermatologic - erythema, nodosum - eye inflammation - oral lesions - gall stones (bile acid malabsorption) *CD can lead to growth retardation in children*

cyclosporine AE

(longer term use more associated with these effects) but since normally only used for approx 2 weeks to induce remission we don't see a lot of a/e - nephrotoxicity - hypertension - hypomagnesemia, hyperkalemia - neurotoxicity (paresthesias, confusion, hallucinations) longer term: - tremor, hyperlipedemia, acne, hirsutism, gum, hyperplasia, leukopenia (rare) - many interactions with CYP450-3A4 inhibitors

S/S UC

(more common on the left side than right as that is where the rectum is) - abdominal pain - frequent bowel movements/diarrhea - tenesmus - mucous/blood in stools if severe disease then systemic symptoms: fever weakness, dehydration, electrolyte abnormalities, tachycardia, anemia ---> general feeling of sickness

What is infliximab used for?

*severe* Crohn's disease and ulcerative colitis

HPA axis suppression

- 'flu-like' symptoms of withdrawal - if CCS are used >2weeks - nausea, anorexia, fatigue, arthralgia, dizziness - best to take oral prednisone in am - a night may suppress early morning ACTH secretions (levels or cortisol usually highest in am and lowest at night)

Crohn's Disease

- *inflammation can be anywhere in the GI tract*, terminal ileum is the most common site - *inflammation crosses all GI layers* - transmural - *lesion distribution is discontinuous - cobblestone appearance* - granulomas and fibrosis are common (clusters of inflammatory cells, can lead to scaring and cause obstructions) - Crohn's colitis - only colon - Crohn's ileitis - only ileum - Crohn's ileocolitis - both ileum and colon

Aminosalicylates

- MOA: anti-inflammatory (unknown mechanism: cyclooxyrgenase inhibition to block prostaglandin production, lipoxygenase inhibition to decrease leukotrienes, inhibition of formation and scavenging of free radicals, interferes with production of inflammatory cytokines) - in IBD used to induce remission (more effective for UC) response in 3-4 weeks - CI in sulfa allergies

S/S CD

- abdominal pain (lower right quadrant most common) - frequent bowel movements, diarrhea - mucous/blood in stools if severe disease then systemic symptoms: fever, weight loss, weakness, dehydration, electrolyte abnormalities ---> "flu-like" symptoms, more likely to occur than in UC

Tumor necrosis factor-alpha antagonists (anti-TNF therapy)

- can be used for UC or CD that has not responded to other therapies - may have maximal effects when used in combination with immunosuppressants - *decrease the need for surgery to treat fistulas* - if patient is responsive for induction then likely will be able to used for remission prevention therapy - infliximab, adalimumab, golimumab, certolizumab

methotrexate AE

- flu like symptoms: nausea, joint pain, fatigue - mucositis - hepatotoxicity - *contraindicated in pregnancy category X* at very high doses: - bone marrow suppression, megaloblastic anemia, alopecia, pulmonary fibrosis

etiology of IBD

- genetic - environmental - lifesyle/diet/smoking - infectious - immunologic (through pro-inflammatory cytokines TNFa or IL-1,2,6,12, epithelial barrier fxn, loss of oral tolerance, ROS, antioxidant defense)

Ulcerative Colitis

- inflammation is restricted to the *colon*, ileum not involved unless backwash "proctitis" - only rectum "left-sided colitis" - sigmoid colon +/- descending colon "pancolitis" - entire colon - inflammation in *first 2 layers of GI tract* - mucosal and submucosal - lesions are *continuous*, may also have necrotic lesions in the crypts *"collar-button lesions"*

complications of UC

- iron deficient anemias - intestinal obstructions - malnutrition/malabsorption - *toxic megacolon* (gas develops as substances can no longer be moved out - can blow up and have potential to perforate the bowel) - colorectal cancer (greater risk after 20y)

nutrition management in IBD

- malnutrition is common therefore nutritional support is important - avoid foods that worsen symptoms (spicy, high fat, caffeine) - pt at risk for osteoporosis should have Ca2+ and VitD supplementation - if bowel rest is required in acute situations TPN (total parenteral nutrition) - fish oils - probiotics

CD complications

- nutritional deficiencies more common - *fistulas* (intestinal, perineal, bladder, vaginal) - greater risk bc all 4 layers of tract affected - structures - bowel obstruction - abscesses - sinus tract infections - renal stones - osteoporosis

surgical management in IBS

- proctocolectomy may be curative for UC - may be complications for CD and require multiple surgeries

UC disease classification

- smokers who quite smoking may have acute flareups of the disease (transdermal nicotine may help)

which 5-ASA products are available as rectal products?

Salofalk = enema, suppository Mezara = suppository, foam (rectal product ONLY) Pentasa = enema, suppository

AE Vedolizumab

hypersensitivity rxns to infusion - headache, nausea, joint pain, fever, fatigue, URT infection, increased LFTs

Dosing for Adalimumab

induction: 160 mg at week 0 and 80 at week 2 maintenance: 40 mg every 2weeks

dosing for golimumab

induction: 200 mg at week 0 then 100 mg at week 2 maintenance: 50 mg every 4 weeks

certolizumab dosing

induction: 400mg at week 0, 2 ,4 maintenance: 400 mg q4w

dosing for infliximab induction and maintenance

induction: 5mg/kg at week 0,2,6 maintenance: q8weeks

pt assessment for IBD

med hx: - pain?location? - diarrhea?characteristics? - weight loss? - extraintestinal manifestations? physical exam: - abdominal tenderness? mass? malnutrition? growth failure in children? lab tests: - ESR and CRP to measure inflammation, also WBCs - albumin - stool cultures - Hg, Fe, B12, folate endoscopy: - location?ulcerations?appearance? biopsy radiology: - barium enema (helps to visualize internal fistulas in CD)--> *contraindicated in severe UC for risk of toxic megacolon

Mezavant

melamine delayed and extended release releases in the terminal ileum and colon available as an oral tablet

Asacol

mesalamine delayed release releases in the terminal ileum and the colon available as an oral tablet

Budenoside

oral (Entocort) - controlled ileal release to deposit predominantly in the ileum and ascending colon - lower systemic bioavailability ---> less side effects - used for CD induction (and remission somewhat) - comparable to prednisone but with less side effects oral (Cortiment) - multimatrix formulation - delayed + extended release - disintegrates throughout colon in a time dependant manner - 9mg qd am - can be used for UC (also CD of colon)

Sulfasalazine

releases in the colon making it better suited for UC or Crohn's colitis

Olsalazine

releases in the colon only, again better suited for UC or crohn's colitis

What is adalimumab used for?

severe CD and UC

what is Golimumab used for?

severe UC

corticosteroid AE

short term: fluid and electrolyte disturbances, hyperglycaemia, increases susceptibility to infections, psychosis, gastric upset long term: HPA axis suppression, osteoporosis, cataracts, muscle wasting, cushion's syndrome (buffalo hump, moon face, ect) depression, PUD, impaired wound healing

What is certolizumab used for?

there is no indication in IBD, but as a TNF-alpha antagonist it is presumed to be efficacious for these disorders

Pentasa

timed release mesalamine product that releases in the duodenum, jejunum, ileum and colon it is available as an oral tablet, enema and suppository

rectal CS

used in moderate to severe UC and CD when the disease is limited to the rectum retention enemas/foams are used when the disease is more extensive and spans beyond the sigmoid colon hydrocortisone rectal products have 15-30% systemic absorption but budesonide has very little options for rectal steroids are: - hydrocortisone enema, form - betamethasone enema - budesonide enema

Cyclosporine

(Neoral) MOA: immunosuppressive, selective inhibitor of T-cell mediated immune response - IV, rapid response in 1-2w - not used as much (severe acute UC or hospitalization)

management of CD

(harder to treat/manage than UC)

aminosalicylate formulations

1) Azo compounds (e.g. Sulfasalazine, Olsalazine) 2) Mesalamine compounds (e.g. Asacol - delayed release, Salofalk - enteric coated, Pentasa - time released, Mezavant - delayed+extended release) may be oral, enemas, suppositories (rectal routes are first choice) - match disease location with site of drug release

Immunomodulators

1) Thiopurines: AZA 6-MP 2) Methotrexate 3) Cyclosporine

Biologic Response Modifiers

1) anti-TNF therapy 2) anti-integrin therapies 3) interleukin antagonists

name the different 5-ASA products

Asacol Mezavant Salofalk Mezara Pentasa

Thiopurines

Azathioprine (AZA), 6-mercaptopurine (6-MP) - MOA: immunosuppressant - slow onset for IBD - 3-6mo - induction and maintenance of remission in both CD and UC - steroid sparing effect

CI for TNF-alpha-antagonista

CI: - pts with bacterial infections - pts with CHF - live attenuated vaccines (MMR) use with caution: - reactivation of infections (TB, HepB) - preexisting demyelinating disorders (MS) - lymphomas

how do entocort and cortiment differ?

Entocort releases mostly in the ileum, whereas cortiment has a mutimatrix formula which allows it to release throughout the colon Entocort is used in mild to moderate active e CD whereas cortiment is used in mild to moderate UC

When are IV CS used?

In the active stage of severe disease in either UC or CD when the pt has either failed on oral prednisone or is hospitalized. We used IV CS to induce remission (use for 3-10 days) and then we want to switch them onto OCS asap so we can begin to taper

Methotrexate

MOA: immunosuppressant, folic acid antagonist - may take 8weeks to be effective - works similar to AZA and 6-MP in CD (unknown efficacy in UC) - given IM or SubQ

Corticosteroids

MOA: non-specific anti-inflammatory and immunosuppressant effects - in IBD is induction therapy for both UC and CD, but has no role in maintaining remission - pt may also have flare-ups when coticosteroids tries to be tapered - 'steroid dependent'

Salofalk

Mesalamine enteric coated released in the terminal ileum and the colon available as a oral tablet, suppository and an enema

Mezara

Mesalamine product that releases in the distal colon and rectum, it is only available as a rectal product in the form of a suppository or foam

corticosteroid formulations

Oral: eg prednisone, 40-60mg/d IV: active severe disease, oral has failed, or hospitalized - require 7-14d for response, then begin taper (5mg qweekly or q1-2d for faster) rectal: when diseases is limited o rectum, e.g. budenoside

aminosalicylates CI

Sulfasalazine: - decreases effect of oral anticoagulants and digoxin - iron will decrease its effects Mesalamine: - decreased digoxin bioavailability

aminosalicylates AE

Sulfasalazine: - due to sulfapyridine moiety (slower acetylators have greater AE) - dose related: nausea, GI upset, diarrhea, anorexia, malaise arthralgia, reticulocytosis - non-dose related: hypersensitivity (rash, fever), pericarditis/hepatitis/pneumonitis/pancreatitis, oligospermia (reversible) - decreases folate levels - folic acid supplementation may be required Olsalazine: - similar to above - most common is diarrhea (minimize by increasing dose slow and take wf) - cross sensitivity with ASA allergy

When are aminosalicylates used?

UC: to induce remission of mild UC and maintenance of moderate and severe UC (in severe they are used along with an AZA or 6MP product) CD: used to induce remission or mild CD (not used much for CD, mostly efficacious in UC)

Interleukin antagonists

Ustekinumab (Stelara) - antagonists for IL12 and 23 - mod-severe CD (for loss/lack of response to TNF-a-antagonists) - IV over 1 hr then sq every 8 weeks (AE = same as above, hypersensitivity to infusion)

Anti-integrin therapy

Vedolizumab (Entyvio) - humanized IgG1 monoclonal antibody to human integrin - used in mod-severe UC/CD (for loss/lack of response to TNF-a-antagonists) - IV, 300mg over 30min 0,2,6 weeks, then maintenance every 8 weeks

Antibiotics

given in short courses for CD with perianal or colonic involvement, or fistulizing disease eg Metronidazole (disulfiram-like rxn for nausea w alcohol), Ciprofloxacin

inflammatory bowel disease (IBD)

a term used to describe two chronic inflammatory diseases of the GI tract: *ulcerative colitis* (UC) and *Crohn's disease* (CD)

AE of TNF-alpha-antagonists

acute infusion reaction: - within 24 hours of infusion - mild pain/itching at injection site, fever, chills, flushing, headache - severe runs include hypotension, chest pain, dyspnea - may pre-medicate with diphenhydramine and acetaminophen delayed hypersensitivity rxn: - *with infliximab* - "delayed infusion rxn" - occurs in 1-2 weeks - serum sickness (fever, hives, malaise, joint pain itching) - if pt experiences then switch to an alternative agent - increased risk of infection - flushing - increased LFTs

thiopurine ITX

allopurinol, febuxostat - inhibit xanthine oxidase (AZA/6MP metabolized by xo) - allopurinol should have a 1/2-1/3 dose reduction - febuxostat should not have concurrent use monitor with CBC/WBC and LFTs

thiopurine AE

dose related: GI (nausea, diarrhea), bone marrow suppression (especially those will low levels of TPMT enzyme for metabolism), hepatic toxicity non-dose related: hypersensitivity (fever, rash, arthralgias), pancreatitis, hepatitis - risk of malignancy (lymphoma and nonmelanoma skin cancers) - pregnancy category D --> but risks likely outweighs benefit if already on the therapy