1
Q
what is crohn’s disease?
A
transmural inflammation of the GI tract that can affect any part from the mouth to the anus
2
Q
what is Ulcerative Colitis?
A
Mucosal inflammation confined to the rectum and colon
3
Q
cytokine dysregulation in CD
A
increased Th1 cytokine activity (interferon gamma, interleukin 12 (IL-12))
4
Q
cytokine dysregulation in UC
A
increased Th2 cytokine activity (IL-12, IL-5)
5
Q
CD diet association
A
refined sugars, low in fruits and veggies, high in w-6 polyunsaturated fats
6
Q
UC diet association
A
high protein
7
Q
how does smoking affect UC and CD?
A
UC– protective? reduced disease activity with fewer flare-ups
CD– increased frequency and severity
8
Q
NSAIDS IBD recommendation
A
generally avoid
9
Q
Drugs that may cause IBD
A
NSAIDS, antibiotics
10
Q
UC pathophys
A
- confined to rectum and colon in the mucosal and submucosal layers
- ulceration and mucosal damage = diarrhea and bleeding
11
Q
UC local complications
A
hemorrhoids, anal fissures, perirectal abscesses
12
Q
toxic megacolon
A
severe and potentially fatal UC complication; segmental or total colonic distention with acute colitis and signs of systemic toxicity
includes:
- increased ulceration depth
- vasculitis and thrombosis
- colonic dilation and/or perforation
- fever, tachycardia, distention, elevated WBCs
13
Q
Other UC complications
A
colonic perforation
massive colonic hemorrhage
colonic stricture
14
Q
colorectal cancer in UC
A
increased risk.
recommend screening colonoscopy with biopsies at 8 years after UC onset, and 1-2 years after that.
15
Q
crohn’s disease pathophys
A
- transmural inflammation
- anywhere in GI tract
- discontinuous
- deep ulcers
- luminal narrowing
16
Q
crohn’s complications
A
- small bowel stricture and obstruction
- fistula (pathogenic connection between bowel and other tissue)
- less bleeding than UC
- some increased carcinoma risk
17
Q
nutritional deficiency in CD
A
- weight loss
- growth failure
- iron deficiency
- vitamin B12
- folate
- hypoalbuminemia
- hypokalemia
- osteomalacia
18
Q
extraintestinal IBD manifestaions
A
- fatty liver, pericholangitis, autoimmune hepatitis, cirrhosis
- primary sclerosing cholangitis, cholangiocarcinoma, cholelithiasis
- iritis, episcleritis, conjunctivitis
- arthritis
- osteoporosis (nutrient deficiency)
- anemia
- coagulation (VTE risk)
- skin and mucosal lesions
19
Q
clinical presentation of UC
A
- abdominal cramping
- frequent BMs and blood and mucous in stool.
- weight loss
- constipation
- fever/tachycardia
- blurred vision, arthritis, dermatologic
20
Q
physical exam findings of UC
A
- hemorrhoids, anal fissures, abscesses
- dermatologic/ocular
21
Q
labs results of UC
A
- decreased Hb/HCT
Increased ESR/CRP - leukocytosis, hypoalbuminemia
- fecal calprotectin (FC) (FC correlates with degree of inflammation)
22
Q
diagnosis of UC
A
confirmed by endoscopy and biopsy
negative stool exam for infectious causes.
23
Q
signs and symptoms CD
A
malaise, fever, abd pain, frequent BMs, hematochezia, fistula, weight loss, arthritis
abdominal mass/tenderness, perianal fissure, fistula
24
Q
Lab tests CD
A
Hb/HCT
Increased WBCs, ESR, CRP
Fecal calprotectin and fecal lactoferrin
+ anti-saccharomyces cervisiae antibodies
25
Clinical presentation CD
variable
typically presents with diarrhea and abdominal pain
hematochezia in ~50%
endoscopy required for diagnosis
26
CD disease classification
mild-moderate: ambulatory; minimal other symptoms; no obstruction CDAI 150-220
moderate-severe: failed therapy for mild-moderate disease. Fever, weight loss, abd pain and tenderness, vomiting, obstruction, anemia. CDAI 220-450
severe-fulminant: persistent symptoms; systemic toxicity; CDAI >450
27
ASA Agents
sulfasalazine and 5-ASA (mesalamine)
28
Sulfasalazine MOA
cleaved by colonic bacteria to release sulfapyridine (inactive) and 5-ASA (active)
29
MOA 5-ASA
local actions
anti-inflammatory
free radical scavenging
30
Mesalamine dosage forms
- rapidly and completely absorbed in the small intestine (not the colon)
- enemas (for left-sided disease)
- suppositories (proctitis)
- delayed/controlled release oral
- can use topical and oral together
31
Oral mesalamine
Apriso: releases in colon 0.375g mesalamine
Lialda: 1.2g mesalamine. released evenly throughout colon.
pentasa: 250 or 500mg. released in duodenum or ileum. dosed QID.
Asacol HD and Delzicol: 800mg (HD) or 400mg (delzicol) released in terminal ileum. TID dosing
Olsalazine (dipentum): 250mg dimer. released by bacteria in colon. BID dosing
Balsalazide (Colazal): Prodrug released by bacteria in colon. (750mg TID)
32
Sulfasalazine ADRs
ADRs due to sulfapyridine
- nausea, vomiting, HA, anorexia, rash (start low-dose)
- anemia, hepatotoxicity, thrombocytopenia
- pneumonitis, lymphoma, nephritis
- hypersensitivity due to sulfonamide
Monitoring: CBCs and LFTs at baseline, every other week for first 3 months, and monthly for second 3 months, and periodically, thereafter. Monitor BUN/Scr periodically.
- interacts with anticoagulants/NSAIDS to increase bleeding risk.
33
Mesalamine ADRs
- better tolerated than sulfasalazine
- nausea, vomiting, HA
- olsalazine: diarrhea
- diarrhea, rash/pruritis, constipation
- anemia, hepatitis/ abnormal LFTs, UC exacerbation
- drug interactions: NsAIDS/antiplatelets/anticoagulants: Bleeding risk
- PPIs, H2RAs, antacids (could influence release of dug in pH dependent dosage forms)
34
Corticosteroids MOA
- anti-inflammatory
(parental for severe exacerbation, oral, or rectal)
- use for remission induction only
rectal dosing: 100-200mg per day (may be absorbed systemically)
35
Budesonide
- PO in CR formulation
- first-pass metabolism (only 9-21% absorbed systemically)
- 6-8mg/day for up to 8 weeks
- Enterocort EC (ileum) and Uceris (colon)
36
Budesonide drug interactions
CYP3A inhibitors (ketoconazole, grapefruit, etc.) May increase systemic exposure.
37
Systemic Corticosteroids
Prednisone or prednisolone 40-60mg/day
- TAPER
- IV methylprednisolone (16-20mg q6h)
- IV hydrocortisone (100mg q8h)
- remission induction only
38
Steroids ADRs
- give calcium and vitamin D while on steroids
- may consider bisphosphonate
- bone mineral density scan occasionally
39
Azathioprine and 6-MP uses
- can be used long-term for both UC and CD
- for patients who fail 5-ASA and dependent on steroids
- can help maintain remission (steroid sparing)
- can use with 5-ASAs, steroids, and TNF-A
- need to use for weeks to months to see benefit
40
AZA and 6-MP dosing
AZA: 0.5-1.5 mg/kg IBW. Max of 2.5 mg/kg/day
6-MP: 0.25-0.5 mg/kg IBW. Max of 1-1.5 mg/kg/day
41
AZA and 6-MP ADRs
- N/V/D, anorexia, stomatitis
- bone marrow suppression
hepatotoxicity
- fever, rash, arthralgia, pancreatitis
monitoring: TPMT, CBC, LFTs
42
Cyclosporine
- can induce remission in IBD (UC)
- Not in CD
- Not for long-term use
- for patients dependent on steroids
initial IV 2-4 mg/kg/day
PO conversion: double IV dose and administered 1/2 Q12H, then taper
43
Cyclosporine ADRs
- nephrotoxicity
- neurotoxicity
- metabolic (HTN, HLD, hyperglycemia)
- GI upset, gingival hyperplasia, hirsutism
44
Cyclosporine monitoring
- BP, BUN/Scr, LFTs, trough concentration
45
Cyclosporine Drug interactions
- CYP3A and PGP substrate
- conc increased due to: azole anti-fungals, macrolide abx, CCBs, grapefruit
- conc dec due to: phenytoin, rifampin
46
Tacrolimus
can be used in refractory disease
47
Methotrexate uses
- Used in Crohns
- steroid sparing, induces remission
- less defined role in UC (combo therapy)
- SubQ or IM
48
Methotrexate ADRs
- bone marrow suppression
- N/V/D, stomatitis, mucositis
- cirrhosis, hepatitis, fibrosis
- hypersensitivity pneumonitis
- rash, urticaria, alopecia
- teratogenic
49
Methotrexate contraindications
- pregnancy
- pleural effusions
- Chronic liver disease (EtOH use)
- immunodeficiency
- leukopenia/cytopenia
- CrCl <40
- blood dyscrasia
50
methotrexate monitoring
CXR, CBC, SCr, LFTs
51
TNF-a antagonists
infliximab (CD and UC)
adalimumab (CD and UC)
golimumab (UC) (go from the colon)
certolizumab pegol (CD) (larissa is a certified a-hole)
52
Natalizumab (tysabri)
- prevents leukocyte adhesion/migration
- Crohn's only
- Natal (friends with natalia?)
53
Vedolizumab
anti-a4b7 integrin antibody
- Both UC and CD
54
IL antagonists
- ustekinumab (stelara) (IL-12 and IL-23) (CD and UC)
- risankizumab-rzaa (Skyrizi) (IL-23) (CD and UC)
- mirikizumab-mrkz (Omvoh) (Il-23 and P19) (UC only)
55
Small molecule drugs
- tofacitinib (Xeljanz) (Oral JAK inhibitor) (UC only)
- upadacitinib (Rinvoq) (Oral JAK1 inhibitor) (UC and CD)
- Ozanimod (Zeposia) (Oral S1P receptor modulator) (UC only)
- estrasimod (Velsipity) (Oral S1P) (UC only)
56
infliximab
UC and CD
- induction and maintenance
- Anti-drug antibody risk
- can combine with immunosuppressives
IV infusion
57
adlimumab
_- UC and CD
- induction and maintenance
- ADA risk
- SQ injection
58
Golimumab
- UC only
- induction and maintenance
- ADA risk
- SQ injection
59
certolizumab
- CD only
- induction and maintenance
- SQ injection
- ADA risk
60
natalizumab
- CD only
- induction and maintenance
- cannot use with immunosuppressants
IV
61
Vedolizumab
- UC and CD
- induction and maintenance
- IV
62
ustekinumab (stelara)
- UC and CD
- IV (induction), SQ (maintenance)
63
risankizumab-rzaa (skyrizi)
- CD and UC
- IV and SQ
- induction and maintenance (moderate to severe)
- avoid live vaccines
64
Mirikizumab-mrkz (omvoh)
- UC only
- induction and maintenance
- IV and SQ
- avoid live vaccines
65
when should TDM be used?
- most data for infliximab and adalimumab
- also check ADA
66
TDM
- therapeutic drug levels no effect (always switch to out of class biologic)
- subtherapeutic levels (detectable ADA's change to alternate drug in same class)
(undetectable ADAs escalate dose)
67
Tofacitinib (Xeljanz)
- Oral JAK inhibitor
- UC only
- intolerant to TNF blockers
- do not use with immunosuppressants
- CYD interactions
- thrombosis risk
- avoid live vaccines
68
Upadacitinib (Rinvoq)
- Oral JAK-1 inhibitor
- UC and CD
- intolerant to TNF blockers
- do not use with immunosuppressants or other biologics
- CYP interactions
- live vaccines contraindicated
- shingles risk
69
Ozanimod (Zeposia)
- S1P receptor modulatory
- UC only
- do not use with immunosuppressants
- Cardiac contraindications
- Bradycardia and AV conduction delays
- Interactions with CYPs, MAO-Is, BB, CCBs, etc.
70
estrasimod (Velsipity)
- s1P receptor modulator
- UC only
- no immunosuppressants
- c/i with caridac conditions
- CYP interactions
- JC virus
71
antimicrobians
- ciprofloxacin, metronidazole, rifamycin
(may cause resistance and C.diff)
72
Mild to moderate UC treatment
- oral and topical ASAs
- Oral if disease extensive
- mesalamine enemas and suppositories
- mesalamine better tolerated than sulfa
- can use oral and topical together!!
73
unresponsive to 5-ASA in Mild-to-moderate active UC
use high-dose mesalamine and rectal mesalamine
74
mild to moderate
- can use budesonide and prednisone
- when non-reponsive to oral or topical 5-ASAs
- typically limit use to short-term
75
moderate to severe active UC
- 4-6 stools/day, blood, and some systemic symptoms
- 5-ASA for moderate (not severe)
- use systemic steroids (prednisone or budesonide)
- consider TNF-a or other biologics when 5-ASA fails and steroid-dependent
76
moderate to severe active UC
TNF-a inhibitors: infliximab, adalimumab, golimumab
antiintegrin: vedolizumab
IL12/IL-23: ustekinumab, mirikzumab, risankizuab
JAK: upadacitinib, tofacitinib (only if fails TNF-a) Black box warnings
SP1 inhibitor: Ozanimod and etrasimod
77
moderate to severe active UC
do not use methotrexate for induction or maintenance; use biologic monotherapy
- use steroids for induction
- may use thiopurine monotherapy for maintenance
- Combine TNF-a with thiopurines or MTX
- discontinue 5-ASA for maintenance
78
Severe UC
- requires inpatient tx
- 6-10 BMs/day
- NPO
- Parenteral steroids (methylpred, hydrocortisone)
- TNF-a (infliximab and cyclosporine)
-cyclosporine and transition to thiopurines (aza or 6-MP)
79
maintenance of remission
- Use ASA (mesalamine) (oral and/or enema) or TNF-a
- azathioprine or 6-MP (Combine with TNF-a to decrease antibodies)
- do not continue steroids
80
mild to moderate crohns
no longer recommend mesalamine derivatives
- use budesonide
- antibiotics
- may use sulfasalazine for mild disease
81
moderate to severe crohns
- steroids
- biologic therapy
- TNF-a (infliximab + AZA or MTX)
- adalimumab + thiopurine (AZA)
- Certolizumab (not first line)
82
Do NOT USE in Crohns
- 5-ASA or sulfa
- Cyclosporine
83
fulminant crohns
steroids, infliximab last line, then surgery
84
CD maintenance of remission
AZA and 6-MP
or SQ MTX
- TNF-a (use with AZA or 6-MP)
- early initiation of biologic in moderate-to-severe disease
85
PHRM 864
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Decks in class (13)
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