3. Rheumatoid Arthritis Flashcards
Main aim of treatment of rheumatoid arthritis
- Relieve pain and inflammation
- Prevent joint destruction
What is rheumatoid arthritis?
An inflammatory autoimmune disease of cellular and humeral components of immunity
5 step potential progression of rheumatoid arthritis
Induction - Caused by genes, host factors and environment
Chronicity - Chronic phase - APC (antigen presenting cells) activate T-cells that activate B cells. Which produce cytokines, chemokines and growth factors.
Effector cells - Macrophages, synoviocyte and osteoclasts
Pathology - Cause inflammation and tissue damage
Outcome - Pain, stiffness, swelling, tenderness
- Deformities and disability
When treating, should we target to treat inflammation and tissue damage
Inflammation - we should never try to target osteoclasts as treatment
Risk factors for Rheumatoid Arthritis
Female - inc by post-partum and breast feeding
Cigarette smoke
What is a pannus?
An abnormal layer of fibrous material
What are the 3 main cytokines involved in the cytokines
TNF alpha
IL-17
TH-17 and TH-1
Role of COX enzyme.
What does each isoform do?
Produce PG from arachidonic acid
COX 1 - Constitutive enzyme found in constant levels and various tissues
COX 2 - inducible enzyme - levels are low in most tissues
What does COX 1 do?
What does aspirin do?
Participates in the synthesis of PG
- Catalyses the formation of TXA2 in the platelets leading to aggregation
- Irreversibly inhibit COX1 by acetylation of the SER529
Role of PG
Cytoprotective effect on the GI tract
What does COX 2 do?
More selective active site there for it has selective binding
- Inhibit the production of prostaglandins
Difference between COX 1 and 2?
COX2 has a larger active site due to a different amino acid sequence. Therefore it is selective to larger inhibitors
Gives anti-inflammatory side effects with less side-effects
- Lower tendency to produce GI bleeding/ peptic ulcers
What is the function of PG and Thromboxane?
PG - E2 and I2 - Pain and inflammation
Thromboxane - TxA2 - Vasoconstriction and inc platelet aggregation - Thrombosis
NSAID side effects and symptoms
GI tract - Heartburn - Dyspepsia - Abdominal pain Serious - Ulceration and bleeding
List NSAIDs by most COX-2 selective to least selective
- Celecoxib
- Meloxicam, Diclofenac etc
- Ibuprofen and Naproxen
- Aspirin
What are the different risks associated with selectivity of COX-2 and COX-1 enzymes
COX-2 - Cardiovascular risk
COX-1 - Gastrointestinal Risk
What MHRA advice has been given for Diclofenac?
Patients with serious underlying heart conditions e.g heart failure, heart disease, circulatory problems or previous MI or stroke should no longer use diclofenac.
Patients that smoke, have high blood pressure , raised cholesterol, diabetes or history of smoking should only use after careful consideration with their GP.
Name 3 never COX-2 Inhibitors
- Etoricoxib
- Parecoxib
- Lumiracoxib
Increased conc of what are found in synovial fluid of patients with RA
IL-1 and TNFa
Roles of IL-1 and TNFa
Act synergistically to increase production of enzymes that degrade components of cartilage matrix
- increase expression of adhesion molecules on endothelium, contributing to the migration of neutrophils and lymphocytes from the circulation
- Stimulate pro-inflammatory mediators e.g IL-8, PGE2 and IL-6§
Pro inflammatory effects of IL-1
increase in:
- ^ TNFa
- ^ Osteoclast activation
- ^ Angiogenic factors
Proinflammatory effects of TNFa
increase in:
- ^ IL-1
- ^ Cell Death
Proinflammatory effects of both IL-1 and TNFa
Increase in:
- ^ COX-2
- ^ PGE2
- ^ NO
- ^ Adhesion Molecules
- ^ Chemokines
- ^ Collagenases
- ^ IL-6
How does RA first present itself?
Stiffness in one or more joints,
- Usually accompanied by pain on movement and by tenderness
List 7 types of criteria for RA
- Morning stiffness
- Arthritis of 3 or more joints
- Arthritis of hand joints
- Symmetric arthritis
- Rheumatoid nodules
- Serum rheumatoid factor
- Radiographic changes to RA
What are rheumatoid nodules, how do we treat?
- Occurs in almost seropositive patients
- Central area of fibrinoid material surrounded by proliferating mononuclear cells
- We do not treat
3 investigatory tests
- FBC - Normochromic/normocytic anaemia and thrombocytosis
- ESR and CRP are raised in proportion to inflammation activity - Radiology - Xray shows joint narrowing or erosion
- Synovial fluid - sterile with high neutrophil count
What 4 blood markers do we look for?
- ESR - The more rapidly the cells settle the more inflammation in the joints - inc in fibrinogen, inc in clotting speed
- CRP - protein produced in the liver when there us inflammation anywhere - more sensitive measure than ESR
- RF - non specific auto antibody found in blood of patients with RA - does not specifically mean that they will have RA
- Anti-CCP antibodies - these are antibodies to proteins altered by inflammation - these are rarely found in patients without rheumatoid arthritis but not always in patients with RA
What is DAS28?
Is it reliable?
- Disease activity score in 28 joints
- provides number on scales 0-10
- High - >5.1
- Medium - 3.2-5.1
- Low 2.6-3.2
- Not always - If only the feet are affected this could be misleadingly low
How do we treat symptoms and flares? Dose?
NSAID or COX-2 inhibitor - Co-prescribe with PPI
- give lowest effective dose
Glucocorticoid therapy - only in flares - not for long term due to SE
Initial treatment
Monotherapy - Conventional DMARDs
- Methotrexate, leflunomide, sulfasalazine
- Can also have hydroxychloroquine, escalate as tolerated
4 suggested MOA for Methotrexate?
Suggested MOA -
- inhibition of purine and pyrimidine synthesis
- supression of transmethylation reactions with accumulation of polyamines
- Reduction of antigen-dependant T-cell proliferation
- Promotion of adenosine release with adenosine-mediated to suppress of inflammation
Why is methotrexate favourable?
Rapid onset (6-8), good efficacy, favourable toxicity profiles, administration and low cost
What is the starting dose for methotrexate? do we monitor?
- 5-10mg orally then inc according to max weekly dose 20mg
- Also take folic acid 5mg to reduce side effects - not on the same day
- Hepatotoxicity and bone marrow
How does methotrexate block purine and pyridine synthesis?
- Inhibition of Dihydrofolate reductase(DHFR) decreases tetrahydrofolte (THF) levels
- Results in attenuated DNA/protein/ lipid methylation
- inhibition of thamidylate synthase (TS) interference with DNA synthesis
- Inhibition of 5-aminoimidazole-4-carboxamide ribonucleotide(AICAR) transformylase blocs de novo purine synthesis
How do we prevent methotrexate toxicities?
Folic acid supplements 1-5mg per day - this gives no impact on the therapeutic effects
What is the typical dose of sulphasalazine? when do we use it?
500mg/day increasing by 500mg weekly to 2-3g a day
added to methotrexate or alone if the patient has methotrexate intolerance
What do we monitor for sulphasalazine?
FBC, urinalysis every 4 weeks - ask patient about skin rash or ulceration within each visit
Side effects for sulphasalazine?
Cough, diarrhoea, nausea, dizziness, fever
What is the mechanism of action for leflunomide?
Inhibition of dihydroorate dehydrogenase(DHODH) leads to decrease rUMP(uridine monophosphate), decreased DNA and RNA synthesis
Inhibition of T-cell proliferation and G1 cell cycle arrest
What is the typical dose for leflunomide?
100mg daily for 3 days then 10-20mg once daily
What are the side effects of leflunomide?
Life threatening liver toxicity in first 6 months
How do we monitor leflunomide?
FBC & FLTs every 2 weeks for the first 6 months
then every 6 weeks
What is hydroxychloroquine?
used to treat palindromic rheumatism
What do we monitor with hyroxychloraquine?
Monitor any visual impairments
What is the typical dose for hydroxychloroquine?
200-400mg daily
max. 6.5mg/kg daily
should only be given on expert advice
Summary of CDMARDs
- Mechanism of action?
- What do they do?
- Side effects?
- Monitoring?
- Time of response?
- Unclear
- inhibit release of inflammatory cytokines
- Majority cause bone marrow and hepatic toxicity
- Full blood count, liver function tests, electrolytes are routinely monitored
- typically 6 weeks to 3 months
What do bDMARDs target?
- TNFa
- IL-6
- T-Cells
- B-Cells
When do we use bDMARDs?
If cDMARDs monotherapy does not work
Name different types of biological agents:
- Monoclonal antibodies -
- Infliximab - Murine
- Adalimumab - Human - Recombinant p75 TNF receptor - Etanercept
- PEGylated Fab’ fragment - Certolizumab pegol
What is sarilumab?
human monoclonal antibody against the IL-6 receptor
What is etanercept?
What is the dose?
what is the SE?
Anti-TNFa agent
- 25mg twice weekly or 50mg once weekly
- injection site reactions, infections and allergic reaction
What is the typical dose for infliximab?
Common adverse effects?
When is it contraindicated?
3mg/kg at weeks 0,2,6 then every 8 weeks
- acute infusion-related reactions, infections, delayed hypersensitivity
- People with moderate or severe heart failure, those withy TB
What is the typical dose for adalimumab?
What does it target?
40mg once every 2 weeks
- TNFa
What does Golimumab target?
TNFa
What is Tolicizumab?
Anti IL-6
What does IL-6 do?
- Cause chronic inflammation - Neutrophils, Macrophage, T-cells
- joint destruction - RANKL
- increased platelets - Bone marrow
- Decreased RBC - Bone Marrow
- antibody production - B-cells
When do we use abatacept?
in combination with methotrexate
- patients with moderate to severe active RA
- patients with insufficient response or intolerance
- including at least 1 TNFa
How do we administer abatacept?
30 minute intravenous infusion
after this it is repeated at week 2, 4 and then every 4 weeks after that
14 infusions in first year - 13 the year after
What is JAK? Give an example
Janus kinase inhibitors
- Tofacitinib - JAK1/JAK3
- Baraicitinib - JAK1/JAK2
What is Rituximab? What does it do?
Genetically engineered chimeric monoclonal antibody
- decreases b-cell targeting cells bearing the CD20 surface marker
When do we use rituximab?
Combination with methotrexate for treatment of adults with severe rheumatoid arthritis with inadequate response or intolerance to other DMARDs including one or more TNF inhibitor
How is Rituximab administered?
Given as two 1000mg IV infusions
- 2 weeks apart
What is the side effects of Rituxumab?
Infections
How does Rituximab work?
TNFa blockade and IL-1 receptor antagonism significantly reduce disease activity
What are the advantages(1) and disadvantages(3) for biological DMARDs?
+ They slow more joint damage than traditional DMARDs
- Expensive - parental route
- Not all patients respond to biological therapy
- More evidence is needed to know true therapeutic value and economic evaluation
Mechanism of action for Tofacitinib - 4 stages
- different cytokines, lymphokines and growth factors signal through cell surface receptor tyrosine kinase
- Activated JAKs phosphorylate STAT
- Tofacitinib as JAK inhibitor prevents phosphorylation of STAT
- Therefore, Prevention of translocation of STAT dimer into nucleus and activation of gene transcription
Biological indicators summary
- Name 8 targets and the drug used to treat
- IL-6 - Tocilimumab
- TNF - Infliximab, Etanercept, adalimumab
- IL-1 - Anakinra
- JAK - Tofacitinib
- RANKL - Denosumab
- CD80 - Abatacept
- CD20 - Rituximab
- SYK - Fostamatinib
