Inflammatory Bowel Disease Flashcards
Inflammatory bowel disease (IBD)
mucosal inflammatory conditions with chronic or recurring immune response and inflammation of the GI tract
Two types of IBD:
ulcerative colitis (UC) and crohn’s disease (CD)
Ulcerative colitis
mucosal inflammation confined to rectum and colon
smoking is a protective factor
more superficical, less likely to see strictures/fistulas
Crohn’s disease
transmural inflammation of GI tract that can affect any part from the mouth to the anus
smoking worsens
not just confined to mucosa, anywhere in GI tract, strictures/fistulas
Etiology
complex multifactorial immune dysfunction
Etiology - drug related causes
NSAIDs: may trigger disease occurrence or lead to flares; unclear whether COX-2 selective agents are associated with a decreased risk
generally avoid NSAIDs in pts with IBD
antibiotics: potential association, however causal relationship unclear
UC pathophysiology
confined to rectum + colon; superficial
biggest sx: substantial diarrhea and bleeding
CD pathophysiology
anywhere in the GI tract (anywhere from mouth to anus)
S/S of UC
abdominal cramping, frequent BMs +/- blood +/- mucous, weight loss, paradoxical constipation, fever/tachycardia, extraintestinal: blurred vision/ocular signs, arthritis, dermatologic manifestations
Lab tests UC/CD
fecal calprotectin (correlates with degree of inflammation) and fecal lactoferrin
more sensitive and specific than serum markers
Diagnosis of UC confirmed by
endoscopy and biopsy
S/S of CD
malaise, fever, abdominal pain, frequent BMs, hematochezia, fistula, weight loss/malnutrition, arthritis
CD sites of inflammation
transmural inflammation - spans entire gut wall
UC sites of inflammation
mucosal inflammation - mucosa or submucosa only
IBD treatment overview
pharmacologic therapy: induction, maintenance
surgical therapy
nutrition support
treatment of complications
avoiding drugs that may exacerbate IBD
Goals of therapy
highly individualized, may include: resolve acute inflammation/treatment of disease flare; resolve and/or prevent complications; maintain remission; alleviate extraintestinal manifestations; avoid need for surgical palliation/cure; surgical palliation/cure; maintain QOL; inducing + maintaining remission
Nonpharmacologic therapy
nutrition support: no specific diet shown to be beneficial; address nutritional deficiencies, impaired absorption: enteral supplementation if necessary, PN (avoid unless absolutely necessary), supplement vitamin/mineral deficiencies (calcium, vit D, folate)
Pharmacologic therapy
no agents are curative!
ASAs (aminosalicylates), corticosteroids, immunomodulators, biologics
ASA meds
sulfasalazine, mesalamine (5-ASA)
Immunomodulator meds
azathioprine, mercaptopurine, cyclosporine, methotrexate
Biologic meds
anti-TNF-alpha agents: infliximab, adalimumab, certolizumab, golimumab
other anti-inflammatory: natalizumab, vedolizumab, ustekinumab
ASA agent - sulfasalazine
sulfapyridine (inactive) + 5-ASA (active ingredient)
5-ASA MOA: anti-inflammatory effects, free radical scavenging
ASA agent - mesalamine
can administer alone
formulation important to deliver to affected area: topical - left sided disease; suppository - proctitis; oral - delayed/controlled release (do NOT crush/chew)
generally topical more effective than oral; can use oral and topical together
Oral mesalamine agents
fairly ineffective in crohn’s
apriso, lialda, pentasa, asacol HD and delzicol, olsalazine, balsalazide (prodrug)
ASA agents - sulfasalazine AEs
sulfapryridine associated with AEs
N/V, HA, anorexia, rash, anemia, hepatotoxicity, thrombocytopenia, hypersensitivity rxns in sulfonamide allergy
drug interactions: antiplatelet/anticoagulants/NSAIDs –> may increase bleeding risk
ASA agents - sulfasalazine monitoring
CBC and LFTs at baseline, every other week for 3mo, monthly for 3mo, periodically thereafter
BUN/Scr periodically
ASA agents - mesalamine AEs
much better tolerated than sulfasalazine
N/V, HA, diarrhea (olsalazine), diarrhea, rash/pruritis, constipation, anemia, hepatitis/abnormal LFTs, UC exacerbation
drug interactions: antiplatelet/anticoagulants/NSAIDs –> may increase bleeding risk
agents affecting gastric pH (PPIs, H2RAs, antacids) -> influence release of drug in pH dependent dosage forms (asacol HD, delzicol)
Corticosteroids
MOA: anti-inflammatory
use for induction of remission but not for maintenance
Corticosteroids - rectal hydrocortisone
suppositories, foam, enema
Corticosteroids - budesonide
PO in CR formulation
extensive first pass metabolism –> minimal systemic exposure
enterocort: dissolves at pH>5.5 (ileum)
uceris: dissolves at pH>/=7 (colon), also available as foam
Corticosteroids - budesonide AEs
possible, but generally well tolerated
drug interactions: CYP3A inhibitors (ketoconazole, grapefruit juice) –> may increase systemic exposure
Systemic corticosteroids
oral prednisone or prednisolone
IV methylprednisolone or hydrocortisone (for very severe disease flare)
may be used for disease flares/induction of remission
Systemic corticosteroids AEs
give calcium and vit D while on steroids; may consider bisphosphonate in pts with risks of osteoporosis, pts using >3mo, or recurrent users
monitor: BP, BG, at baseline and q3-6mo, consider occasional bone mineral density scan (DEXA)
Short and long term systemic corticosteroid AEs
short term: hyperglycemia, gastritis, mood changes, increased BP
long term: aseptic necrosis, cataracts, obesity, growth failure, HPA suppression, osteoporosis
Azathioprine and mercaptopurine
can be effective in long term tx of UC and CD - generally reserved for pts who fail 5-ASA tx and/or pts refractory/dependent on steroids
can maintain remission, steroid sparing, limited role in induction of remission
can be used with otehr drugs (5-ASAs, steroids, TNF-alpha)
AZA is a prodrug rapidly converted to 6-MP
Azathioprine and mercaptopurine AEs
N/V/D, anorexia, stomatitis, bone marrow suppression, hepatotoxicity, fever, rash, arthralgia, pancreatitis
Azathioprine and mercaptopurine monitoring
TPMT (pharmacogenomic testing); CBC qwk for 1st month, q1-2wks after dose change, q1-3mo after; LFTs
Cyclosporine
can be effective inducing remission in pts with refractory IBD (not recommended for CD)
not an option long term
IV infusion –> PO
Cyclosporine AEs
nephrotoxicity, neurotoxicity, metabolic (HTN, hyperlipidemia, hyperglycemia), GI upset, gingival hyperplasia, hirsutism
Cyclosporine monitoring
BP qvisit; BUN/SCr q2wks until stable, then periodically; LFTs q2wks until stable, then periodically; cya tr. conc goal ~200-400ng/ml
Cyclosporine drug interactions
substrate for CYP3A and P-glycoprotein
increase cyclosporine conc: azole anti-fungals, macrolide antibiotics, CCB, grapefruit
decrease cyclosporine conc: phenytoin, rifampin
Tacrolimus
used in refractory disease, role less defined
Methotrexate
used in CD for tx and maintenance - steroid sparing effects, assist in inducing remission, allow steroid-tapering
SC/IM
Methotrexate AEs
bone marrow suppression (add folic acid 1mg/day), N/V/D, stomatitis, mucositis, cirrhosis, hepatitis, fibrosis, hypersensitivity, pneumonitis, rash, urticaria, alopecia, teratogenic*
Methotrexate monitoring
CXR, CBC, SCr, LFTs
maintenance q4-8wks
Methotrexate contraindications
pregnancy, pleural effusions, chronic liver disease/EtOH abuse, immunodeficiency, preexisting blood dyscrasias, leukopenia/t.cytopenia; CrCl < 40 ml/min
Biologics: TNF-alpha antagonists
infliximab: CD + UC
adalimumab: CD + UC
golimumab: UC
certolizumab: CD
Biologics: other - natalizumab
natalizumab: anti-alpha-subunit of integrin’s (prevents leukocyte adhesion/migration); CD
Biologics: other - vedolizumab
anti-alpha4beta7 integrin antibody; CD + UC
Biologics: other - IL inhibitors
ustekinumab: IL-12 and IL-23 antagonist; CD + UC
risankizumab-rzaa: IL-23 antagonist; CD + UC
mirikizumab-mrkz: IL-23 p19 antagonist; UC
New small molecule drugs: JAK inhibitors
tofacitinib: UC
upadacitinib: CD + UC
New small molecule drugs: S1P receptor modulators
ozanimod: UC
estrasimod: UC
TNF-alpha inhibitors AEs
increase risk of serious infections - tuberculin test, CXR, Hep B/C prior to therapy and ensure vaccines up to date (live vaccines contraindicated); injection site rxns and infusion related rxns; risk of malignancy (lymphoma); hepatosplenic T-cell lymphoma risk; risk of demyelinating disease; may exacerbate CHF
TNF-alpha inhibitors monitoring
CXR, PPD, s/sx of infection, UA, CBC, SCr, lytes, LFTs, Hep B/C
maintenance q8-12wks
TNF-alpha inhibitor: infliximab
CD + UC - induction and maintenance therapy, can be used for fistulizing disease
IV infusion
development of antibodies to infliximab - combining with immunosuppressive (azathioprine) may be of value (and may increase risks of AEs)
Infliximab AEs/monitoring
hepatosplenic T-cell lymphoma risk
infusion related rxns
monitor: s/sx of infection, vitals (each dose), infusion rxns (each dose), therapeutic drug monitoring (TDM)
TNF-alpha inhibitor: adalimumab
CD + UC
use for pts with poor response to infliximab
induction + maintenance therapy
SQ injection - self administered
Adalimumab AEs/monitoring
development of ADAs (antidrug antibodies)
TDM possible
TNF-alpha inhibitor: golimumab
UC
induction and maintenance therapy
SQ injection - self administered
Golimumab AEs/monitoring
development of ADAs
TDM possible
TNF-alpha inhibitor: certolizumab pegol
CD
induction and maintenance therapy
SQ injection - self administered
Certolizumab AEs/monitoring
development of ADAs
TDM possible
Natalizumab
anti-alpha subunit of integrin’s (prevent leukocyte adhesion/migration)
non-specific MOA, does it at other sites in body (i.e. CNS)
CD - inducing and maintaining remission
can use in pts who fail/don’t toelrate TNF-alpha inhibitors; NOT to be used in combo with immunosuppressants, TNF-alpha inhibitors
IV
Natalizumab AEs/monitoring
associated with progressive multifocal leukoencephalopathy (PML) - able to test for JC antibody; increased risk with: longer duration of therapy, prior immunosuppressant use, JC antibody +; monitor closely for neurological events
hypersensitivity rxns, ADAs
Vedolizumab
anti-alpha4beta7 integrin antibody - gut specific
CD + UC - inducing and maintaining remission, decreasing steroid dependence
IV
Vedolizumab AEs/monitoring
hypersensitivity rxns, ADAs, infection, PML monitoring bc of similar MOA to natalizumab
TDM possible
Ustekinumab
IL-12 and IL-23 antagonist
CD + UC
IV induction, SQ maintenance
Ustekinumab AEs
hypersensitivity (anaphylaxis and angioedema); ADAs; rapidly developing cutaneous cell carcinoma in pt with risk factors; neurotoxicity (reversible posterior leukoencephalopathy syndrome, posterior reversible encephalopathy syndrome)
TDM possible
Ustekinumab monitoring
CXR, PPD, Hep B/C, lipids 1-2mo after start then periodically, LFTs 1-2mo after start then periodically, renal fx, s/sx of infection, skin
Risankizumab-rzaa
selective IL-23 antagonist
CD + UC - induction (IV) and maintenance (SQ)
use lowest dose possible
Risankizumab AEs
HA, nasopharyngitis, arthralgia, abdominal pain, anemia, nausea, infections/latent infections (TB) (vaccines necessary, avoid live ones), hypersensitivity, ADAs, hepatotoxicity, increase in lipids
Risankizumab monitoring
CXR, PPD, Hep B/C, lipids 1-2mo after start then periodically, LFTs 1-2mo after start then periodically, renal fx, s/sx of infection
Mirikizumab-mrkz
IL-23p19 antagonist
UC - induction (IV) and maintenance (SQ)
Mirikizumab AEs
HA, arthralgia, rash, injection site rxn, infections/latent infections (TB) (vaccines necessary, avoid live ones), upper respiratory tract infections*, hypersensitivity possible, ADAs, hepatotoxicity
Mirikizumab monitoring
CXR, PPD, Hep B/C, lipids 1-2mo after start then periodically, LFTs 1-2mo after start then periodically, renal fx, s/sx of infection
TDM of biologics
potential for determining concentrations of drugs and ADAs
consider if loss of treatment response (use reactively, not proactively)
check ADA concurrently; optimal trough concentrations not clear
Detectable/undetectable ADAs
subtherapeutic drug levels - detectable ADAs: change to alternate drug, within same class; if no ADAs: dose escalate
therapeutic drug levels - detectable ADAs: switch to out of class biologic agent; no ADAs: switch to out of class biologic agent
JAK inhibitor - tofacitinib
approved for UC only - who have had an inadequate response or who are intolerant to TNF blockers; option for pts who fail biologics
use lowest effective dose to maintain response
rapid onset; do NOT use with immunosuppressants or biologics
Tofacitinib AEs
diarrhea, elevated cholesterol, HA, herpes zoster, increased creatine phosphokinase, nasopharyngitis, rash, URI; increased risk of infections (vaccines, no live ones)
rare: malignancy, serious infection, neutropenia, hypersensitivity (angioedema, urticaria)
black box warning: increase mortality in RA pts with at least one CV risk factor; thrombosis –> increased risk in RA pts with at least one CV risk factor
Tofacitinib monitoring
CXR, PPD, Hep B/C, ANC q3mo, CBC q1-2mo then q3mo, lipids 1-2 months after start then periodically, LFTs 1-2mo after start then periodically, s/sx of infection, skin exam
JAK1 inhibitor: upadacitinib
oral selective JAK1 inhibitor
CD + UC - who have had inadequate response or who are intolerant to TNF blockers; pts who fail biologics; should NOT be used with immunosuppressants or biologics
rapid onset
Upadacitinib AEs
black box warning similar to tofacitinib; increased risk of serious infection (vaccines, no live ones); upper respiratory tract infection, acne, increased creatine phosphokinase, elevated cholesterol, HA, herpes zoster
rare: malignancy (lymphoma), serious infection, increased LFTs, anemia, neutropenia, lymphopenia, hypersensitivity (angioedema, urticaria), teratogenic*
Upadacitinib monitoring
CXR, PPD, Hep B/C, ANC/ALC q3mo, CBC q1-2mo then q3mo, lipids 1-2wks after start then periodically, LFTs 1-2wks after start then periodically, s/sx of infection, skin exam
S1P receptor modulator: ozanimod
oral selective spingosine-1-phosphate recpetor modulator: prevents lympocyte mobilization to inflammatory sites
UC only - if dose missed in 1st 2wks of tx, reinitiate titration regimen
do NOT use with non-corticosteroid immunosuppressive or immune modulating drugs
Ozanimod contraindications
if in last 6mo experienced: MI, unstable angina, stroke, TIA, decompensated HF, class III or IV HF, type II 2nd or 3rd degree AV block, sick sinus syndrome, or SA block (unless functioning pacemaker), severe untreated sleep apnea, taking MAO inhibitor
Ozanimod AEs
increased risk of infections (PML) - vaccinate against varicella, no live vaccines; bradycardia/AV conduction delays; liver injury/elevated transaminases (not recommended in pts with LFTs >5fold upper limit of normal); increase in systolic BP; respiratory effects; macular edema; reversible posterior leukoencephalopathy syndrome/posterior reversible encephalopathy syndrome
Ozanimod drug interactions
adrenergic and serotonergic drugs
combo beta blocker and CCB
foods high in tyramine
MAO inhibitors
Ozanimod monitoring
CXR, PPD, Hep B/C, CBC periodically, LFTs periodically, s/sx of infection, BP each visit, spirometry, ECG, optho
S1P receptor modulator: estrasimod
oral selective spingosine-1-phosphate receptor modulator - prevents lymphocyte mobilization to inflammatory sites
UC
do NOT use with non-corticosteroid immunosuppressive or immune-modulating drugs
Estrasimod contraindications
in last 6mo experienced: MI, unstable angina, stroke, TIA, decompensated HF, class III or IV HF, various cardiac conduction abnormalities
no same warnings regarding MAO inhibitors as oxanimod
Estrasimod AEs
increased risk of infections (PML) - vaccinate against varicella (no live vaccines); bradycardia/AV conduction delays; liver injury/elevated transaminases; increase in systolic BP; macular edema; reversible posterior leukoencephalopathy syndrome/posterior reversible encephalopathy syndrome; respiratory effects
Estradimod monitoring
CXR, PPD, Hep B/C, CBC periodically, LFTs periodically, s/sx of infection, spirometry, ECG, optho
Mild-moderate active UC tx overview
left sided disease: enemas
proctitis: suppositories
extensive disease, pancolitis: systemic tx
Mild-moderate active UC: oral/topical ASAs
extensive disease: oral 5-ASA
left sided disease: topical mesalamine enema
proctitis: mesalamine suppository
combo of oral + topical in left-sided/extensive disease
if unresponsive to 5-ASA can change formulation or increase dose/combo therapy
Mild-moderate active UC: alternatives
CR budesonide when nonresponsive to oral or topical 5-ASA
PO corticosteroids (prednisone) in pts refractory to ASAs (not for maintenance!)
topical corticosteroids effective for distal disease
remember: combo oral and topical mesalamine can be more effective
Moderate-severe UC tx overview
4-6 stools/day, +/- blood in stool, some systemic sx
5-ASA therapy possible for moderate, not severe
systemic corticosteroids (PO prednisone), for moderate can use oral budesonide
consider TNF-alpha inhibitors/biologics in pts unresponsive to ASAs/other therapy or who fail steroids
use methotrexate for induction or maintenance
thiopurine monotherapy only for maintenance
combine TNF-antagonists, vedolizumab, or ustekinumab with thiopurines or MTX rather than monotherapy
suggest early use of biologics
Severe-fulminant UC tx overview
inpatient tx; consider NPO
parenteral corticosteroids: methylprednisolone or hydrocortisone for 3-7 days, then transition to PO
TNF-alpha inhibitors (infliximab) or cyclosporine in pts unresponsive to IV steroids
UC maintenance of remission tx overview
use ASA, TNF-alpha antagonist (infliximab and adalimumab), azathioprine, or 6-MP
no role for corticosteroids!
ASAs: mesalamine better tolerated than sulfasalazine
if unresponsive to ASA, use azathioprine or 6-MP
TNF-alpha antagonist for pts who required one for induction or fail azathioprine
Mild-moderate active CD tx overview
sulfasalazine (not great efficacy)
do NOT use mesalamine
controlled release budesonide for ilealeocecal or right-sided disease
Moderate-severe active CD tx overview
failed tx for mild-mod disease or having systemic sx
systemic corticosteroids (PO prednisone) - treat until resolution of sx; hospitalized pts may receive IV corticosteroids (methylprednisolone, hydrocortisone)
early biologic therapy - TNF-alpha antagonists (inflizimab + AZA; adalimumab), also use the other biologics
immunomodulator (AZA and 6-MP) monotherapy not recommended to induce remission, can be used for maintenance of remission; MTX for induction and maintenance
do NOT use cyclosporine, 5-ASA, sulfasalazine
Severe-fulminant CD tx overview
inpatient tx; consider NPO; supportive care
parenteral corticosteroids (methylprednisolone or hydrocortisone, treat 3-7 days, then transition PO)
infliximab may be preferred if fulminant
CD maintenance of remission
sulfasalazine and PO mesalamine (not for mod-severe)
NO role for systemic corticosteroids
budesonide minimal long-term efficacy, don’t use for >4mo
AZA and 6-MP are effective; MTX alternative to AZA and 6-MP
TNF-alpha antagonists are options: use of infliximab or adalimumab in combo with AZA or 6-MP
