Inflammatory Bowel Disease (UC + CD) Flashcards
Define inflammatory bowel disease
mucosal inflammatory conditions with chronic or recurring immune response and inflammation of the gastrointestinal tract
What are the two types of IBD?
ulcerative colitis
crohn’s disease
Define UC
mucosal inflammation confined to rectum and colon
Define CD
transmural inflammation of GI tract that can affect any part from the mouth to the anus (deeper inflammation)
CD etiology
increased Th1 cytokine activity (interferon gamma, interleukin 12 [IL-12])
UC etiology
Increased Th2 cytokine activity (IL-13, IL-5)
smoking and UC
potentially protective
smoking and CD
increased frequency and severity of CD
NSAIDs and IBD
doesn’t really cause the disease but can make symptoms worse
Antibiotics and IBD
doesn’t really cause the disease but can mess with flora and exacerbate symptoms
UC pathophysiology
confined to the rectum and colon and affects mucosal and submucosal layers (its more superficial than CD)
abscess formation in mucosal crypts, coalescence results in ulceration
ulcers can surround normal tissue
mucosal damage –> substantial diarrhea and bleeding
UC complications
local, systemic, extraintestinal complications
local: hemorrhoids, anal fissures, perirectal abscesses
Major complications: colonic perforation, massive colonic hemorrhage, colonic structure
UC Toxic megacolon
severe and potentially fatal complications
segmental or total colonic distention (> 6cm) with acute colitis and signs of systemic toxicity
increased depth of ulceration
vasculitis and thrombosis
colonic dilation and potential perforation
UC Toxic megacolon symptoms
fever, tachycardia, abdominal distention, elevated WBCs, abdominal distention on radiograph
UC pathophysiology: colonic dysplasia/colorectal cancer (CRC)
risk of colonic dysplasia w/ transition to CRC is 5x greater in UC
cumulative risk of CRC is up to 20 - 30% at 30 years
Screening colonoscopy with biopsies recommended at 8 years after UC onset and every 1 - 2 years after that
CD pathophysiology
transmural inflammation
can occur anywhere in the GI tract
often discontinuous (normal bowel separating diseased bowel)
deep, elongated ulcers, cobblestone appearance
bowel wall injury may be extensive, associated with luminal narrowing
Where most common to see CD in GI tract?
terminal ileum
CD Pathophysiology Complications
small bowel stricture and obstruction possible
fistula common (20 - 40% lifetime risk)
less bleeding than UC (anemia is possible)
Risk of carcinoma is increased (not as high a risk as UC)
nutritional deficiencies: wt loss, growth failure in children deficiencies (iron deficiency anemia, vitamin B12, folate), hypoalbuminemia, hypokalemia, osteomalacia
Extraintestinal Manifestations of IBD: Bone and Joint
arthritis –> asymmetrical, migratory, typically involves one/few large joints
may be at increased risk for metabolic bone disease and osteoporosis (nutritional deficiencies: Ca and vitamin D, inflammation, hypogonadism, use of corticosteroids)
Extraintestinal Manifestations of IBD: Hematologic
anemia (prevalence up to 74%): iron deficiency, anemia of chronic disease, blood loss
Extraintestinal Manifestations of IBD: Coagulation***
1.5 - 3.6x increase risk of VTE
higher during flares, consider prophylaxis if admitted for flare
Extraintestinal Manifestations of IBD: Dermatologic and Mucocutaneous
variety of skin and mucosal lesions
Clinical Presentation of UC
highly variable
abdominal cramping
frequent BMs +/- blood +/- mucous
wt loss
paradoxical constipation possible
fever/tachycardia
extraintestinal: blurred vision/ocular signs
hemorrhoids, anal fissures
UC Laboratory Tests
decreased Hb/HCT
Increased ESR/CRP
leukocytosis, hypoalbuminemia (severe dz)
***fecal calprotectin (FC) and fecal lactoferrin (FC correlates with degree of inflammation, more sensitive and specific than serum markers)
diagnosis made on clinical suspicion and confirmed by endoscopy and biopsy
UC: disease extent determined by ____________
endoscopy
4 ways to classify a UC patient
remission
mild (< 4 stools, intermittent blood, normal hemoglobin)
moderate-severe (> 6 stools, frequent blood in stools, Hgb < 75% normal)
fulminant (> 10 stools, continuous bloody stool, required transfusion)
Clinical Presentation of CD
highly variable, characterized by periods of remission and exacerbation
typically diarrhea and abdominal pain (hematochezia in ~50% of patients)
Dx involves clinical evaluation in addition to endoscopic (upper and lower), laboratory, radiologic testing
malaise, fever, abdominal pain, frequent BMs, wt loss
CD Laboratory Tests
Hb/HCT
increased WBCs, ESR, CRP
fecal calprotectin and fecal lactoferrin
(+) anti-saccharomyces cervisiae antibodies (routine use not recommended)
CD Disease Classification
no global classification
CDAI (Crohn’s disease activity index): Used most frequently in research to gauge response to therapy and determine remission
How to classify CD***
Mild-moderate: ambulatory with minimal other Sx (dehydration, systemic toxicity), CDAI 150 - 220
Moderate-severe: patients who fail therapy for mild-moderate disease or those with fever, wt loss, abdominal pain/tenderness, vomiting, obstruction, anemia (here is where you really start to see Sx), CDAI 220 - 450
Severe-fulminant: persistent Sx or evidence of systemic toxicity despite corticosteroid or biologic tx or presence of cachexia (wasting disease), CDAI > 450
IBD Tx Overview
highly individualize. May include:
- resolve acute inflammation/tx of disease flare
- resolve and/or prevent complications
- maintain remission
- alleviate extraintestinal manifestations
- avoid need for surgical palliation/cure
Want to get patients off of steroids~!
Inducing remission is an important aspect of therapy
IBD nutrition support
no specific diet shown to be beneficial
address nutritional deficiencies (avoid parenteral nutrition unless absolutely necessary)
some benefit with probiotic therapy
Nonpharmacologic therapy: Surgery
resecting areas of inflammation
colectomy rates in UC ~ 5 - 30% (may be necessary if failed pharmacologic therapy)
surgery indications for CD are less established
Certolizumab pegol (Cimzia)
only for CD
SQ injection
for mod-severe active CD
we do see the development of antibodies against these drugs
Natalizumab (Tysabri)
anti-alpha-subunit of integrin’s (prevents leukocyte adhesion/migration)
CD: induces and maintains remission
NOT used in combo w/ immunosuppressants
ONLY for CD
used in pts who fail TNF-alpha inhibitors
d/c in pts w/ no benefits by 12 weeks –> associated w/ progressive leukoencephalopathy (PML) –> the activation of a latent virus –> can be rapidly debilitating or fatal. can test pts for JC antibodies
drug is non specific
Vedolizumab (entyvio)
related to natalizumab
inhibits alpha 4 beta 7 subunit which is gut specific
targets lymphocytes active in the gut –> safer than natalizumab
for UC and CD
same ADRs as other biologics
NOT associated w/ PML (still monitor neurological changes)
Ustekinumab (stelara)
for both UC and CD
IL-12 and IL-23 specific
dosed IV (wt based induction) and subQ
ADRs similar as other biologics
unique ADR: rapidly developing skin cancer, possible neurotoxicity (PRES, typically stops once d/c drug)
TDM (therapeutic drug monitoring is possible)
For biologics…
…monitor tx response after start to see lack of response. Check [ ]
ADA
anti-drug antibodies
Tofacitinib (Xeljanz) - NOT A BIOLOGIC
Newer small molecule drug
oral Janus kinase (JK) inhibitor
UC only (for pts who had inadequate response/can’t tolerate other therapies like TNF inhibitor)
serious ADR, poorly tolerated, can be associated w/ neutropenia. Black box warning (2): increase mortality in RA pts 50 years and older w/ at least one CV risk factor AND thrombosis (PE, DVT, Arterial) in RA pts 50 years and older w/ at least one CV risk factor
rapid onset
do not use with other immunosuppressants or biologics
if pt has renal impairment, maybe avoid this drug
don’t use with strong CYP3A4 inhibitor, but if you do, decrease dose by 50%
Ozanimod (Zeposia)
just approved in May of 2021!
oral selective sphingosine-1-phosphate (S1P) receptor modulator. prevents lymphocyte mobilization to inflammatory sites
moderate-severe UC only
7 day dose titration
contraindicated in pts who had previous CV events, pts w/ sleep apnea, in pt’s taking MAO inhibitor
21 hour half life
metabolized by ALDH/____ —> dont use in pts with hepatic impairment
theoretical PML risk
make sure pt is vaccinated
we see increases in ALT 5 fold upper limit of normal. If LFTs have a > 5 fold increase, d/c drug
associated with Hypertensive crisis
has an active metabolite, avoid using with MAO inhibitors
co-administration with CYP2C8 inducers + inhibitors –> can increase active metabolite –> coadministration not recommended
antimicrobials role
if pt has CD and they have fistulas and abscesses, use anti-microbials as adjunctive tx
worry about Clostridium difficile because it mimics other Sxs
sulfasalazine (ASA Agent)
sulfapyridine (a sulfonamide) + 5-ASA (mesalamine)
sulfapyridine is inactive but associated with ADRs
5-ASA is the active component (MOA = include anti-inflammatory effects, free radical scavenging)
Mesalamine (ASA Agent)
CAN administer mesalamine alone
rapidly and completely absorbed in small intestine BUT NOT COLON
generally topical is more effective than oral
can use oral and topical together
Topical (enema) mesalamine for
left-sided disease
Suppository mesalamine for
proctitis (inflammation of the rectum lining)
Oral mesalamine for
delayed/controlled release
examples
- Apriso releases in colon and dissolves at >/= pH 6
- Lialda releases evenly throughout colon (terminal ileum) at pH >/= 6.8
- Pentasa releases in duodenum and ileum, up to 60% of dose reaches colon
- Asacol HD and Delzicol dissolves at >/= pH 7. releases in terminal ileum
- olsalazine (dipentum) released after colonic bacteria cleaves bond, release in colon
- Balsalazide (colazal) released after colonic bacteria cleaves bond, releases in colon
Apriso releases in
colon
Lialda releases in
terminal ileum
Pentasa releases in
duodenum, ileum
Asacol HD, Delzicol releases in
terminal ileum
Osalazine releases in
colon
Balsalazide releases in
colon
sulfasalazine is associated with
ADRs (really NO reason to continue using this)
> 10%: N/V, HA, anorexia, rash
<10%: anemia, hepatotoxicity, thrombocytopenia
hypersensitivity rxns in sulfonamide allergy
always titrate slowly
sulfasalazine monitoring parameters
CBC, LFTs, BUN/Scr
sulfasalazine drug interactions
antiplatelet/anticoagulants/NSAIDs –> may increase bleeding risk (ASA)
mesalamine _____________ than sulfasalazine
much better tolerated
common SEs: N/V, HA
up to 80% of pts intolerant to sulfasalazine will tolerate mesalamine
mesalamine drug interactions
antiplatelet/anticoagulants/NSAIDs –> may increase bleeding risk (ASA)
agents affecting gastric pH (PPIs, H2RAs, antacids) –> could influence release of drug in pH dependent dosage forms
Corticosteroids used for ____________ but not for _____________
remission; maintenance
corticosteroids = anti-inflammatory
can be parenteral, oral or rectally
rectal hydrocortisone:
- suppositories, foam, enema
- note that systemic absorption is possible with rectal formulations
Budesonide General Information
administered PO in CR formulation
first pass metabolism –> minimal systemic exposure
6 - 8 g
8 weeks (16 weeks)
Enterocort (brand) dosage form dissolves at PH > 5.5
Uceris (brand) dissolves at pH >/= 7. both PO and a foam
Budesonide drug interactions
CYP3A4 inhibitors –> may increase systemic exposure
ADRs: similar to other glucocorticoids but it is generally well-tolerated
Systemic Corticosteroids
must taper
parental typically for in-patients
*may be used for disease flares/induction of remission
give Ca and vitamin D while on steroids. may consider bisphosphonates in pts w/ osteoporosis
monitoring: occasional bone mineral density scan (DEXA) in pts > 60
Oral Corticosteroids
Prednisone, Prednisolone
IV Corticosteroids
Methylprednisolone, hydrocortisone
Azathioprine (AZA) and Mercaptopurine (MP, 6-MP) facts
can be effective in long term tx of UC and CD
Do not induce but can MAINTAIN remission
generally reserved for pts who fail 5-ASA and/or patients who are refractory to/dependent on steroids
b4 initiating, check genetics, check TPMT
Azathioprine (AZA) and Mercaptopurine (MP, 6-MP) not recommended for…
…MONOTHERAPY
AZA is a…
pro-drug that is rapidly converted to 6-MP
AZA and 6-MP ADRs
GI: N/V/D, anorexia, stomatitis
hematologic: BONE MARROW SUPPRESSION
hepatic: hepatotoxicity
idiosyncratic: fever, rash, arthralgia, pancreatitis
AZA and 6-MP monitoring
TPMT (anything other than wild type = adverse effects)
CBC
LFTs
Cyclosporine facts
common in transplant patients
effective inducing remission in pts w/ refractory IBD
NOT recommended for CD
Not for long term use
NOT COMMON for IBD
Cyclosporine ADRs
nephrotoxicity (dose related)
neurotoxicity
metabolic (HTN, hyperlipidemia, hyperglycemia)
other: GI upset, gingival hyperplasia, hirsutism
Cyclosporine monitoring
BP
BUN/Scr
LFTs
Cya tr. conc
Cyclosporine drug interactions
substrate for CYP3A4 and P-glycoprotein
drugs/foods that increase cyclosporine concentrations: azole anti-fungals, macrolide antibiotics, ca channel blockers, grapefruit and grapefruit juice
drugs that decrease cyclosporine concentrations: phenytoin, rifampin
Tacrolimus and IBD…
used in refractory disease although role is less defined
Methotrexate (MTX) facts
can be used in CD. may have steroid sparing effects
MTX ADRs
hematologic: bone marrow suppression (add folic acid 1 mg/day)
GI: N/V/D, stomatitis, mucositis (1mg folic acid)
hepatic: cirrhosis, hepatitis, fibrosis
pulm: hypersensitivity pneumonitis
derm: rash, urticaria (hives), alopecia
ALSO MTX IS TERATOGENIC
MTX contraindications
pregnancy
pleural effusions
chronic liver disease/EtOH abuse
immunodeficiency
preexisting blood dyscrasias
leukopenia/t. cytopenia
CrCl < 40 ml/min
MTX monitoring
CXR, CBC, Scr, LFTs
infliximab (Remicade)
anti-TNF alpha antibody
CD and UC
adalimumab (Humira)
anti-TNF alpha antibody
CD and UC
golimumab (Simponi)
human monoclonal anti-TNF-alpha antibody
UC
certolizumab pegol (Cimzia)
human pegylaged anti-TNF alpha Fab fragment
CD
natalizumab (Tysabri)
anti-alpha-subunit of integrin’s (prevents leukocyte adhesion/migration)
CD
vedolizumab (Entyvio)
anti-alpha-4-beta-7 integrin antibody (alpha-4-beta-7 integrin is expressed on subset of T-lymphocytes)
UC and CD
ustekinumab (Stelara)
IL-12 and IL-23 antagonist
CD and UC
Name the two small molecule drugs
ozanimod (Zeposia)
tofacitinib (Xeljanz)
ozanimod (Zeposia)
oral sphingosine-1-phosphate (S1P) receptor modulator
UC
tofacitinib (Xeljanz)
oral Janus kinase inhibitor (JK) inhibitor
UC
Do NOT initiate TNF-alpha inhibitors during…
…active infections
TNF-alpha inhibitor ADRs
increase risk of serious infections (bacterial, viral, fungal)
live vaccines contraindicated during tx and for 3 mo after
risk of malignancy
hepatosplenic T-cell lymphoma (HSTCL) risk
risk of demyelinating disease
may exacerbate CHF
Monitoring for TNF-alpha inhibitors
CXR, PPD, S/S infection, UA, CBC, Scr, lytes, LFTs, Hep B, Hep C
Infliximab (Remicade)
UC and CD (both moderate to severe)
development of antibodies to infliximab –> decreased tx response
combining with immunosuppressives may be of value
hepatosplenic T-cell lymphoma (HSTCL) risk
infusion related reactions
Adalimumab (Humira)
UC and CD (both moderate to severe)
*can use for pts with poor response to infliximab
can lead to the development of ADAs (human-derived, potentially less likely than infliximab)
Golimumab (Simponi)
UC (moderate to severe)
can lead to the development of ADAs (human-derived, potentially less likely than infliximab)
TDM possible: > 2.5 - 3.8 mcg/ml (week 6) and > 1.4 - 2.4 mcg/ml (maintenance)
