Module 3: IBD Digavalli Flashcards
Dr, Digavalli EXAMV
Affected areas of Inflammatory Bowel Disease (IBD) vs Crohn’s disease
IBD: starts in the rectum -> may affect the entire colon continuously
Crohn’s disease: non-continuous, patchy areas, often the ileocecal junction; may affect large or small intestine
Which layers of the tissues are affected?
IBD: superficial -> limited to the mucosal layer
Crohn’s: affects multiple layers -> may lead to strictures, perforation, fistula formation
Characteristics of Crohn’s disease
-skip lesions or cobblestone patterns
-transmural lesions: affecting multiple layers -> leading to strictures, perforation, fistula
What are diseases that arise as a consequence of IBD?
-risk of colorectal cancer (regular colonoscopy recommended)
-Extra GI:
skin
dry eyes
Arthropathy
Arthritis
thromboembolic events
stricture of the bile duct (in Chron’s disease)
Disease progression in IBD
-symptoms wax and wane but with gradual damage to the GI with each episode (flares)
-damage: strictures, fistula, abscesses
Possible progression to IBD
- Genetic predisposition and environmental factors (hygiene, diet, smoking)
- disease: infection, drug use (NSAIDs damaging the gut wall or antibiotics killing good bacteria) ->
- bacteria crossing the wall and causing an inflammatory reaction -> uncontrolled immune response (interleukin, TNF)
- bowel damage, tissue remodelling -> IBD
Mild treatment options
-5-amino salicylates (5-ASA; mesalamine)
-topical corticosteroids (proctitis)
-budesonide (ileitis)
-antibiotics
5-amino salicylates (mesalamine)
-for mild IBD
-MOA not clear
-works locally in the gut
-Sulfasalazine is broken down to 5-ASA (mesalamine) ->
-5-ASA forms an azo linkage -> 5-ASA derivates which is not very well absorbed (stays in the GI)
-bacteria’s azole reductase breaks up the azole linkage -> RELIEF
What is the supposed MOA of 5-ASA
-prostanoid release -> NFκB suppression
-NFκB stimulates cytokine production
Which drug has different formulations to target specific areas of the GI?
5-ASA derivates
DDS approaching such as enteric coating (protection against gastric dissolution or early release in the small intestine)
MOA of Glucosteroids
-binds glucocorticosteroid receptor -> deactivating transcription factors
-prevents the synthesis of inflammatory proteins
-suppress inflammatory signals (NFκB)
What is the severity of IBD treated with glucocorticoids?
Mild, moderate IBD
moderate/severe flares
-after treating flares -> patients switch to other drugs bc of the side effect profile
Side effects of Glucocorticosteroids
-susceptibility to infections (due to immune suppression)
-interfere glucose metabolism -> gluconeogenesis from non-carbon source -> increases glucose level
-lipid levels go up (via lipolysis)-> arteriosclerosis
-Cushing syndrome (moon face)
Other side effects of steroids
-Hypothalamus -Pituitary gland -Adrenal medulla axis -> constant cortisol release -> HPA insufficiency bc the steroid mimics the cortisol -> the body thinks there is enough cortisol and stops producing cortisol (inhibiting the HPA-axis), may cause depression
-osteoporosis
-glaucoma
-muscle myopathy
-hirsutism
-skin breakage
-gastric ulcer (with NSAIDs)
Glucocorticoids drugs
Oral, IV when severe
-Prednisone (prodrug)
-Prednisolone (active part)
-Budesonide (synthetic, less systemic due to high first-pass metabolism)
Why is budesonide often preferred over prednisone(prednisolone?
-higher metabolism by 3A4 (avoid grape juice)
-less systemic effects
-the effect on cortisol level is less -> lowering the risk of HPA insufficiency
Which drugs are substituted with steroid drugs
Purine anti-metabolites (azathioprine and 6-MP)
-also for steroid-resistant/dependent patients
-maintain remission while transitioning from steroids
-take weeks to be efficacious
MOA of purine anit-metabolites
-interfering with fast-dividing white blood cells
-mimic adenine and guanine
azathioprine (prodrug) ->
6-mercapto purine (prodrug) -> 6-thioguanine (active drug)
How does Xanthine oxidase affect Purine anti-metabolites?
-Purines are metabolized by Xanthine oxidase in the liver
-XAO processes DNA breakdown products into uric acid -> which deposits in joints causing GOUT
-DDI in gout/hyperuricemia patients taking Allopurinol (purine analog) blocking XAO -> less purine antimetabolite metabolism -> higher concentration and TOXICITY
-> reduce dose by 25%
Contraindications of Purine-antimetabolites
Pregnancy
since they interfere with DNA synthesis
MOA of Methotrexate
-Anti-metabolite of folic acid (IBD, cancer,..) - mimics folic acid
-interferes with folic acid metabolism: used to synthesize DNA
-Methotrexate interferes with DNA synthesis by blocking the dihydrofolic acid reductase
(also used in adjunction for biologics -> preventing Antidrug-antibodies (ADA))
MOA of Cyclosporine
-Inhibits Calcineurin (Ca++/Cam-dependent
phosphatase) involved in immune signaling
-not first line
-used to bridge from steroids
Which drugs are used for steroid transitioning?
-Purine anti-metabolites: azathioprine and 6-MP)
-Methotrexate
-Cyclosporine (short-time bride to 6-MP)
What is the role of TNF, INF and interleukins?
- dendritic cells -> antigen presentation to CD4 TH cells
- IL12/23 for TH differentiation -> Th1 and Th2 are pro-inflammatory (via IFN-gamma and IL- 12/4) and Treg is anti-inflammatory (via TGF-ß and IL-6)
- TNF-alpha and IFN-gamma for macrophage activation
- integrins for lymphocyte and monocyte migration from the blood
What severity of IBD is treated with anti-TNFs?
-moderate to severe flares in IBD
-patients resistant to other therapies
-neutralize soluble and tmTNF
-all mAbs are parenterally (IV, SC)
-cleared by proteolysis
-latent infection may activated (TB (give prophylactic INH), fungal infections)
What happens to the affected cell when anti-TNF binds to tmTNF?
complement fixation and cell lysis
What mitigates the efficacy of anti-TNFs over time?
Antidrug-antibodies (ADA)
-co-administration with methotrexate may help
-switch to another anti-TNF (mAb)
How do anti-integrins work?
-integrins are present on lymphocytes
-TNF stimulates selectin synthesis in endothelial cells
-lymphocytes will bind to selectins and stop at the site of infection
-anti-integrins-antibodies block the integrin-selectin interaction -> no homing of lymphocytes
Examples of anti-integrins
-Natalizumab (Tysabri)
-Vedolizumab
-only used when other anti-TNFs don’t work
-approved for MS and Crohn’s disease (reduces inflammation)
Which side effect to look out for in anti-integrins
-multifocal leuko-encephalopathy (not common)
(infection of the gray matter in the brain)
-Vedolizumab doesn’t cause it
Which drug class does Ustekinumab belong to?
anti-IL 12/23 mAb
-IL12/23 for TH differentiation
-2nd line drug for Crohn’s disease (when steroids and anti-TNF failed)
-low risk of latent infection activation
What drug class does Tofacitinib (Xelijanz) belong to?
Janus Kinase (JAK) inhibitors
-inhibits the JAK/STAT pathway (prevents phosphorylation and translocation of STAT into the nucleus)
-downregulates the production of cytokines
-it is NOT an antibody
-for Ulcerative Colitis
-can activate latent infections
Which drugs may activate latent infections?
-anti-TNFs (Infliximab, Adalimumab, Certolizumab, Golimumab)
-Tofacitinib (Xelijanz) - JAK/STAT inhibitors
Common drugs causing a decrease in microbiome diversity
-PPIs
-Metformin
-Antibiotics
-NSAIDs
-Laxative
Countering bacterial dysbiosis
-Prebiotic: food for probiotics
Asparagus, Banana, garlic, wheat bran
-Probiotics contain “good” gut bacteria:
E. coli, Lactobacilli, Bifidobacteria found in
-> Yogurt, sour cream, probiotic milk, kefir
