Targeting inflammation: Rheumatoid arthritis Flashcards
1
Q
What is rheumatoid arthritis?
A
-An autoimmune inflammatory disease where our immune cells infiltrate our joints.
- Principally affect the synovial joints.
- Antibodies produced include: rheumatoid factor & antibodies against post-translational modified proteins (ACPA)
2
Q
What is inflammation?
A
- An essential defence system that is highly regulated by our immune system to help protect our tissues from injury/ infection.
- In RA, inflammation is unchecked and leads to tissue damage.
3
Q
Discuss acute vs chronic inflammation.
A
- Acute:
- Response to infection or trauma
- Vasodilation allows immune cells access the site of infection
- Inflammation also triggers healing.
- It is then terminated by production of resolvins - Chronic:
- Failure to terminate inflammation leads to chronic inflammation.
- Resulting in tissue damage and fibrosis.
4
Q
What does inflammation resolution entail?
A
- Removal of pro-inflammatory mediators
- Neutrophil apoptosis
- Release of pro-resolving mediators
- Transformation of M1 (inflammatory) macrophages to M2 (phenotype)
5
Q
Discuss inflammatory pain.
A
- Inflammatory mediators such as PGs, 5HT and bradykinin sensitise pain fibres.
- Rather than cause pain they sensitise pain fibres making them more likely to respond to other pain signals
6
Q
What is the role of local mediators in inflammation and pain?
A
- Local mediators include prostaglandins, leukotrienes, PAF, histamines etc.
- They are secreted by immune cells.
- Responsible for the symptoms of inflammation such as vasodilation.
- Pain happens when inflammation occurs near a pain fibre.
7
Q
What is the mechanism of action NSAIDs?
A
- Used to treat inflammation.
- They act to inhibit cyclooxygenase and prostaglandin production.
- They are anti-inflammatory, analgesic and anti-pyretic.
8
Q
What are the adverse effects of COX inhibition?
A
- Gastric ulceration:
– Due to COX inhibition in stomach
– Responsible for protective mucus layer - Bleeding problems
– COX activates platelets
9
Q
Discuss COX 1 and COX 2.
A
- They are very similar: 65% AA sequence homology and near-identical catalytic sites.
- Most significant difference between the isoenzymes, which allows for selective inhibition, is the substitution of isoleucine at position 523 in COX-1 with valine in COX-2.
10
Q
What influence does valine in COX-2 have?
A
- Valine (smaller) allows access to hydrophobic pocket in enzyme which Isoleucine sterically hinders.
- Drugs like Rofecoxib bind to this alternative site and is considered to be a selective inhibitor of COX-2.
11
Q
Discuss COX-2 inhibitors.
A
- E.g. celecoxib and rofecoxib.
- Developed to protect against Gastric Ulceration.
- Similar efficacies to that of the non-selective inhibitors, decreases GIT effects by 50%.
- Associated with reduced prostaglandin I2 (PGI2 / prostacyclin) production by vascular endothelium.
- Little or no inhibition of potentially pro-thrombotic platelet thromboxane A2 production.
- Therefore an exaggerated prothrombotic effect will be observed in patients treated chronically with Coxibs!
12
Q
When are NSAIDs contraindicated?
A
- All NSAIDS except Naproxen appear to increase cardiovascular risk.
- The increased risk is dose dependent.
- Avoid NSAID use in patients at high risk of cardiovascular event.
- Use lowest dose for shortest period.
13
Q
Is paracetamol an NSAID?
A
- No. Used in fever & pain not inflammation.
- MOA unclear:
- Thought to be COX 2 selective inhibitor.
- Its major metabolite NAPQI activates TRPA1 in the spinal cord producing anti-nociceptive response.
- Help control pain without impacting neutrophil function and prevent development of chronic pain.
14
Q
Discuss glucocorticoids.
A
- Increase lipocortin production which inhibits phospholipase A2.
- Reduces the production of IL-1 and 2, interferon, prostaglandins and leukotrienes.
- Decreases basophils, eosinophils and monocytes, lymphocytes but increase in neutrophils.
- Adverse effects on carbohydrate metabolism.
15
Q
Discuss sulfasalazine.
A
- Developed for treatment of “infective poly-arthritis”.
- Anti-inflammatory: Salicylic Acid.
- Antibiotic: Sulfapyridine
- Salicylic acid and sulfapyridine joined by an azo bond.
- Reduced by the bacterial enzyme azo reductase to sulfapyridine and 5-amino-salicylic acid (5-ASA) in bowel
16
Q
What is Sulfasalazine MOA?
A
- Active moiety is 5-amino-salicylic acid not sulfapyridine
- MOA unclear:
1. Affects neutrophil activity,
2. Reduced production of IL-1,
3. TNF from monocytes/macrophages,
4. Inhibits T-cell proliferation etc.
17
Q
What are the adverse effects of Sulfasalazine?
A
- These are primarily due to sulfapyridine. Include:
– Skin reactions,
– Hepatitis,
– Pneumonitis,
– Agranulocytosis,
– Aplastic anaemia
– Males - oligospermia and infertility
– GI upset less severe haematological toxicities
18
Q
Discuss Hydroxyquinone.
A
- Anti-malarial medication found useful for the treatment of inflammatory arthritis.
- MOA unclear - penetrate cell walls and stabilise lysosomal membranes.
- Inhibit metabolism of deoxyribonucleotides.
- Interferes with cell’s ability to degrade and process proteins.
19
Q
What are the common side effects of Hydroxyquinone?
A
– Rash, nausea, diarrhoea
– Ocular – retinopathy/colour vision - rare but requires monitoring
– Depigmentation
– Myopathy
20
Q
What are the drugs that target IL-1?
A
- Anakinra soluble recombinant IL-1RA can be used to inhibit action of IL-1
- Approved for use in rheumatoid arthritis (RA) - Canakinumab
- Multiple autoimmune disease including RA
- Blocks anti-IL-1β antibodies - Gevokizumab
- Development on hold
- Blocks anti-IL-1β antibodies - Rilonacept
- Used for some orphan indications
21
Q
Discuss the use of B cell depletion in RA.
A
- B-Cells cannot act as antigen presenting cells to activate T-Cells
- B-Cells cannot produce Rheumatoid Factor
- B-Cells cannot release cytokines
22
Q
Discuss Rituximab.
A
- Monoclonal antibody to CD20 (B cell surface marker).
- Specific for B-cells.
- Triggers complement formation and cell lysis.
- Used to treat: B cell lymphoma and RA resistant to anti-TNF therapy.
- Patients can develop fatal SIRS & PML
23
Q
Discuss the pathway that Rituximab opsonised B cells are subject to attack.
A
Via at least three pathways:
1. Complement
2. Direct lysis
3. Fcy receptor mediated opsonic phagocytosis of ADCC
24
Q
Discuss Tofacitinib.
A
- Janus kinase (JAK) 1 mediates signalling from some cytokine receptors.
- Tofacitinib is a small molecule inhibitor of JAK1.
- Only used as under a REMS (risk EVAL.)
- Limitations of use:
1. Not recommended to be used in combination with biologic DMARDs or potent immunosuppressants such as azathioprine and cyclosporine.
2. ^ risk of serious infections.
2. People with known malignancies.
3. Lab abnormalities: lymphocytes, neutrophils, hb & lipids to be monitored.
25
Q
List the approved RA drugs.
A
26
Q
What are disease modifying drugs?
A
- Disease modifying Anti-Rheumatic drugs (DMARDs).
- Disease modifying agents in MS.
- Disease modifying drugs act to:
1. Symptom Control (control inflammatory features)
2. Modify the course of disease: - Reduce joint damage and deformity
- Reduce radiographic progression
- Reduce long-term disability
- Reduce the progression of MS symptoms
- Reduce number of lesions by MRI in MS
27
Q
Discuss disease modifying anti-rheumatic drugs (DMARDSs).
A
28
Q
Discuss therapeutic strategies in RA.
A
- Symptomatic treatment for immediate pain relief
- Early use of DMARDs
- Start with Mono-therapy – ideally Methotrexate
* If Mono-therapy doesn’t work
– Combinations of Conventional DMARDs
– Combinations of DMARD plus Biologic agents
29
Q
Discuss the symptomatic treatment of RA.
A
- NSAIDs.
– Symptomatic relief, improved function
– No change in disease progression - Low-dose prednisone (<10 mg qd)
– May substitute for NSAID
- Used as ‘bridge therapy’
– If used long-term, add Ca, Vit D, or bisphosphonates for osteoporosis risk
– Possible disease modifying effect - Intra-articular/parenteral steroids
– For flares of symptoms
30
Q
Discuss the common DMARD combinations.
A
- Triple Therapy
– Methotrexate,
– Sulfasalazine,
– Hydroxychloroquine - Double Therapy
– Methotrexate & Sulfasalazine
– Methotrexate & Hydroxychloroquine
– Sulfasalazine & Plaquenil - If all else fails - Biologic Therapy
31
Q
Define gout.
A
- A monosodium urate crystal deposition disease.
- Metatarsal phalangeal joint at the base of the big toe is most often affected.
- May also present as tophi, kidney stones, or urate nephropathy.
- Caused by elevated uric acid levels in the blood, an end product of purine metabolism and present in the serum and tissues in the form of monosodium urate (MSU).
- With prolonged tissue deposition , gouty arthropathy and tophi develop.
- Also increased risk with age.
32
Q
Describe the treatment strategies for gout.
A
- Prevention of inflammation/ acute attack
- NSAIDs
- Colchicine
- Corticosteroids - Decrease synthesis of urate
- Allopurinol - Increase excretion of urate
- Probenecid
- Rasburicase
33
Q
Discuss Colchicine.
A
- Extracted from plant Colchicum.
- Anti-inflammatory: reduces inflammatory response to deposited crystals
- Interferes with neutrophil function (binds to
tubulin leading to micro-tubular depolymerisation) - Diminishes PMN phagocytosis of crystals
- Blocks cellular response to deposited crystals.
- Used in both acute and chronic gout.
34
Q
Discuss colchicine toxicity.
A
- GI:
- Nausea, vomiting, cramping, diarrhoea, abdominal pain - Haematological:
- agranulocytosis, aplastic anaemia, thrombocytopenia, neutropenia - Hair loss:
- Due to inhibition of mitosis. - Muscular weakness
**Adverse effects are dose-related & more common when patient has renal or hepatic disease.
35
Q
What is Allopurinol?
A
- A xanthine oxidase inhibitor which is administered orally.
- Used to treat hyper-uricemia (excess uric acid in blood plasma) and its complications, including chronic gout.
- It does not alleviate acute attacks of gout
- Useful in chronic gout to prevent future attacks.
36
Q
Discuss the food with low, moderate and high purine levels.
A
