Week 5 & 12 - IBD, Cancer and Inflammation Flashcards
How does the immune system cause disease?
- Trigger can causes immune response leading to inflammation within the body
List some immune-mediated inflammatory diseases (IMIDs)
- Rheumatoid arthiritis
- Asthma
- Inflammatory bowel disease
What is Inflammatory bowel disease (IBD)
-Is chronic (continuous) inflammation of gastric mucosa ~ eventually alters structure of GI tract
-Its unpredictable ~ have relapses + remission
Refers to 2 intestinal conditions:
1. Crohn’s disease
- whole GI tract can be affected (i.e. from mouth to anus)
Common symptom
- STRICTURES = bowel obstruction (due to narrowed segments of bowel = blockages)
- FISTULAS = part of GI tract fuse together = narrowing (+ channels lined with granulation tissue)
2. Ulcerative colitis
- only affects mucosa of large intestine (bowel, colon, rectum)
- common symptom = bleeding
Common symptom = diarrhoea, abdominal pain, bloating, weight loss,
Risk factors: diet, smoking, medicine, stress, genetic
How can you manage inflammatory bowel disease?
AIM:
- achieve + maintain remission
- improve QoL
- reduce complications
- Medicines
- combination drugs often used (some drugs which induce remission don’t maintain it)
- therapeutic drug monitoring is required
- corticosteroids, aminosalicylates, antibiotics, immunomodulating agents - Nutritional supplemets
- calcium + vitamin D = prevent risk of osteoporosis and provides bone protection - Biologics & Targeted cell therapy
- Surgery
- Newer approaches - novel approaches
- Faecal microbiota transplant
- transfer gut micro-organisms from healthy donor into intestinal tract of IBD patient
- Probiotics - Vaccinations
- Influenza
- Pneumococcus
- Covid-19
How does corticosteroids manage IBD?
e.g. prednisolone, hydrocortisone ~ oral, topical, IV)
- Induce remission but doesn’t prevent progression / complication = not maintenance med.
- Used in UC and CD
- Reduce inflammation + modulate immune system
- Prednisolone MoA: bind to glucocorticoid receptors + inhibit inflammatory cells + suppress expression of inflammatory mediators
- Can develop corticosteroid dependancy
- See improvement within few days
- 2nd gen c.steroids have high affinity for intracellular glucocorticoid receptor in GI tract
- Rectal glucocorticoids useful in UC
Side effects:
- hypertension
- increased appetite
- GI effects
- infection risk due to suppression of immune system
- cant stop abruptly (= adrenal suppression), need to ween of steroid
Why are co-prescribed medicines used alongside corticosteroids to manage IBD?
- PPI given alongside corticosteroids
- Provide gastro protection due to potential GI side effects
- Calcium + vitamin D supplements
- Provide bone protection + prevent osteoporosis (brittle / fragile bones) risk
Dieticains may support IBD patients
Nutritional status of patient is assessed
How do aminosalicylates manage IBD?
- Induce +maintain remission (in UC)
- High dose = treat flare up and lower dose = maintenance
- Topical (rectal) + oral preparations can be given = more effective
- topical can be: suppository, foam, enema - MoA: have anti-inflammatory action (reduced inflammation in GI tract), decrease prostaglandin production (in colon), inhibit production of pro-inflammatory cytokines
- E.g. Sulfasalazine, Balsalazide, Mesalazine
- Monitor response to treatment for signs of flare up (+ renal function, blood dyscrasias)
Side effects: abdominal pain, diarrhoea, nausea, rash, blood dycrasias, report unexplained bleeding, bruising, fever, mouth ulcers etc.
MoA = Mechanism of Action
How do Immunomodulators manage IBD?
Immunomodulators - suppress immune response + inflammation = reduced GI tract inflammation
- Thiopurines
- 1st line option, they induce (w/ c.steroid use) + maintain remission
- Can take 3-6 months for full effect
- MOA: reduces inflammation in GI tract
- Use weight dosing (start lower then can increase)
- Active metabolite can be monitored if treatment isn’t going as expected
- TMPT levels must be measured before treatment begins (TMPT = enzyme involved in metabolism of drug, low levels have increased risks of myelosupression)
Side effects: myelosupression, hypersensitivity, liver disorder, nausea, diarrhoea (GI)
- Need to regularly do full blood counts + liver function test - Methotrexate
- Maintenance in CD
- Given once weekly (with folic acid) - Ciclosporin
- Given IV
- Induces remission in severe UC - Biologic / targeted cell therapies
How do biologics & targeted cell therapy manage IBD?
- Used when conventional options haven’t worked / contra-indications
- Biologics
- Are monoclonal antibodies what bind to cytokine (TNF ~ this mediates inflammatory response)
- Inhibits inflammatory effect in gut
- Used in UC and CD (moderate to severe)
- E.g. Infliximab, Adalimumab
Infliximab:
- given by IV infusion
- may have infusion reactions
- pre treatment screening compulsory (includes Hep B / C, HIV, TB)
Adalimumab
- given by SC injection
- can be administered at home
- better tolerated due to no infusion related risk
- pre treatment screening compulsory
Other biologics examples
Ustekinumab (interleukin inhibitor)
- Blocks interleukin-12 (IL-12) and interleukin-23 (IL-23)
- Used in UC and CD
- Initial IV infusion then SC injection
- Risk of reactivation of infections and malignancy
Vedolizumab
– Inhibits leucocyte migration to parenchymal tissue in the gut
- Reduces inflammation
- Used in UC and CD
- IV and SC formulations
- Risk of reactivation of infections and malignancy
Tofacitinib (JAK inhibitor)
- Disrupt phosphorylation of JAK enzymes on cytokine receptors, inhibiting inflammatory pathways
- Used in UC
- Extra monitoring required
- Concerns due to increased VTE risk in some patients
How to identify & diagnose IMID
- Blood tests
- Stool culture
- Faecal calprotectin
- Abdominal imaging
- Colonoscopy
- Endoscopy
- Biopsies
- Truelove and Witts’ severity Index - for UC
- Crohn’s disease activity index (indexes assess multiple variables)
How does local anatomy & physiology influence formulation choice?
- Different formulation will release drug in diff. parts of bowel
What is cancer
- Uncontrolled cell division / growth
- Mutation occurs and when missed by body checkpoints, allows more mutations (hallmarks) to occur = uncontrolled growth
- When mutation is detected by body cell goes through apoptosis
- Cancer cells can form tumour at 2nd site if get into circulation
- cancer therapy is targeted to primary tumour, more difficult tote eat when cancer has spread
What does a cell need to become cancerous
7 Hallmarks
1. Insensitive to growth inhibitors
2. Produce own growth signals
3. Divide / replicate uncontrollably (acquire mutation)
4. Sustained angiogenesis
5. Evade apoptosis
6. Tissue invasion + metasisis
7. Inflammatory microenvironment2
Need to be able to evade normal immune mechanisms that destroy abnormal cells
Cancer cells produce signals which attract immune cells to tumour microenvironment to promote tumour growth
Cancer caused by “2 hit” hypothesis
- Mutation + inflammation / multiple mutations= cancer
- Single mutation / inflammation on own = no cancer
- Mutations lead to an “initiated cell” - more mutations = preneoplastic cell - progresses into neoplastic (cancer) cell
How is inflammation linked to cancer?
Inflammation supports:
1. Initial formation of cancer
- its a tumour promoter + causes genetic mutations = DNA damage
- Creates reactive oxygen species + reactive nitrogen species which damage DNA
- Produces inflammatory cytokines + growth factors
- cytokines change epigenetic mechanism (turns genes on in cells meant to be off in)
- Working in chronic inflammatory environment = more mutation
2. Growth of cancer cells
- Inflammation supports tumour invasion, immune suppression, angiogenesis (new blood vessels), tumour proliferation, matrix remodelling
- Above processes are controlled + switched off when skin / wound etc. heals BUT In tumour processes carry on continuously
- Produces molecules which suppress immune system (PDGF = blood vessels can form)
- T cells, macrophages, dendritic cells produce cytokines + chemokine which support survival, growth, invasion, proliferation and angiogenesis
- Positive feedback: immune cells send signal to cancer cells, cancer cells tell immune cells to make more
3. Metastasis
- Inflammation supports opening of endothelial cells = cancer can spreads
- Degradation of the ECM
- Primary tumour sends signals to body to prepare secondary site (signal attracts circulating tumour cells)
- Intravasion + extravasion
4. Response to therapy
Inflammation on its own DOESN’T cause cancer, it exploits existing mutations
It produces factors which supports all aspects of cancer
Cancer cells modify immune system
