Treatments for RA Flashcards
1
Q
How many people have RA in the UK
A
400,000 people with RA in the UK
Approx. 12,000 new cases diagnosed each year
1% of UK population
2
Q
what does synovitis of RA affect
A
- the joint
- tendon sheaths
- other body organs such as increased coronary artery disease
3
Q
What joints are affected in RA
A
- small joints of hands and feet
- symmetrical
- in severe cases most joints will be affected over time
- alanto axis joint can also be damaged
4
Q
describe how you diagnose RA
A
Joint involvement
- 1 large joint = 0
- 2-10 large joints = 1
- 1-3 small joints = 2
- 4-10 small joints = 3
- > 10 joints (at least 1 small joint = 5
Serology
- Negative RF and negative ACPA = 0
- Low positive RF or low positive ACPA = 2
- High positive RF or high positive ACPA = 3
Actue phase reactants
- Normal CRP and normal ESR = 0
- Abnormal CRP or abnormal ESR = 1
Duration of symptoms
- <6 weeks = 0
- > 6 weeks = 1
have great than or equal to 6/10 for diagnosis
5
Q
What are the two things that you are trying to treat in RA
A
- pain relief
- modification of disease progression
6
Q
how do you treat pain relief in RA
A
- Follow guidelines as for OA
- Analgesics and NSAIDs
- COX-2 inhibitors
7
Q
What do you start of in treatment of disease modification of progression in RA
A
Disease modifying anti-rheumatics DMARDs
- Conventional DMARDs
- “Biologicals”
8
Q
What are the two types of DMARDs
A
- Conventional DMARDs
- “Biologicals”
9
Q
What does DMARDs stand for
A
Disease modifying anti-rheumatics
10
Q
what is the adjunct therapy that can be used for modification of disease progression in RA
A
adjunct therapy = oral corticosteroid pulse
11
Q
describe the treatment pathway for RA
A
pain manegement (newly diagnosed RA) - NSAIDs and narcotics(opioids)
First line disease treatment mild RA
- Methotrexate and second line DMARD
Second line disease treatment (moderate RA)
- methotrexate and TNF alpha inhibitor therapy
Second line disease treatment (severe RA)
- Methotrexate and rituximab
Novel disease treatments (unmanageable RA)
- Surgical interventions
12
Q
What is the gold standard for RA treatment
A
methotrexate
13
Q
what are the non pharmacological treatment that can be used for RA
A
- Physiotherapy
- occupational therapy
- podiatry
- therapy (relaxation, stress management, coping)
14
Q
if you are newly diagnosed with RA what treatment should you get
A
Combination of DMARDs
- Methotrexate and at least one other DMARD plus short term glucocorticoids
If combination not appropriate (comorbities or pregnancy)
- DMARD monotherapy
- you should cautiously reduce the dosage to the level that still controls the disease
15
Q
what is the only autoimmune disease that effects males more than females
A
Anklyisng spondlytisis
16
Q
why should you not give a DMARD to pregnant women
A
- Drugs are often toxic and tetragenic
17
Q
what is the 1st choice drug in RA
A
Methotrexate
18
Q
when should methotrexate be given
A
Orally once a week on the same day
- 2.5mg tablets
- Start between 5-10mg a week
- If oral form does not work subcutaneous or intramuscular injection
19
Q
How long does methotrexate take to work
A
3-12 weeks before benefit seen
20
Q
what are the side effects of methotrexate
A
- can cause live problems
- can affect blood count
these need to be monitored every month to check to see if they are still working
21
Q
How does methotrexate works
A
- folic acid antagonists
- methotrexate enters the cell through the folate carrier
- glutamate it added to it and it becomes polyglutamted within the cell
- it inhibits dihydrofolate reductase
- thus blocking the conversion of dihydrofolate to tetrahydrofolate
- this blocks synthesis for RNA and DNA
- also inhibits thymidylate synthetase
22
Q
what type of drug is methotrexate
A
- it is an antimetabolite - prevents the cell from replicating
- normally given as an anticancer drug
23
Q
What is sulfasalazine
A
- Antibiotics
- combines sulfapyridine and salicylate with azo bond
24
Q
how do you take sulfasalazine
A
Orally
- Start at 500mg daily
- Gradually increased over 4 weeks to 1g twice a day
25
How long does it take sulfasalazine to work
12 weeks before benefits are noted
26
where is sulfasalazine absorbed
Not well absorbed across the gut
- Less than 15% of parent drug
- Metabolised by gut bacteria and these are better absorbed in the gut submucosa
27
describe the pathway of sulfasalazine
- sulfasalazine is convereted to 5 ASA in the large intestine
- then it combines its sulfapyrdine and forms N-actetyltransferase 2
28
What does sulfasalazine usually treat
- treats ulcerative colitis
| - also relieves arthritic symptoms
29
describe how sulfasalazine works
- donuts get absorbed and helps prevents local GI inflammation by reducing the amount of proinflammatory cytokines that can get into the blood
- these pro inflammatory cytokines can also affect the joint
- inhibits IL-1 and TNF alpha these both cause inflammation in the gut
- also inhibits COX, LOX, PAF, cytokines
30
what type of drug is hydroxychloroquine
Anti-malarial drug
31
how do you give hydroxychloroquine
Oral with or after food
- Start 400mg daily
- Reduced to 2-3 times a week
32
How long does it take for the benefits of hydroxychloroquine to work
12 weeks for benefit
33
how does hydroxychloroquine work
- Accumulates in lysosomes increasing the pH decreasing protein modifications
- Blocks Toll-like receptor 9 which recognises DNA containing immune complexes decreases activation of dendritic cells
34
What is the negative of hydroxychloroquine and why should you never give it to a person with Psoriasis
= can get nasty rash on flexor department
| - shouldn't be given to anyone with a rash that it makes the rash worse
35
describe how lefunomide works
- inhibits pyrimidine biosynthesis by inhibiting dihydroorotate dehydrogenase (DHODH)
- This blocks DNA and RNA synthesis
36
How should lefunomide be given
10-20mg a day
| - 1st 3 days higher dose 100mg a day
37
what is the efficacy of lefunomide similar to
methotrexate
38
how does D pencillamine work
Copper chelator
Thought to decrease immune response and IL1 generation
Preventing maturation of newly synthesised collagen prevents collagen cross linking (prevent fibrosis)
39
what are the side effects of D pencillamine
Kidney damage – monitor for proteinuria
40
how often do you give gold salt IM injections
- 50mg
| - 4-6 months before effects are seen
41
do DMARDs act broadly
yes
42
what type of biologicals can you use to treat RA
inhibition of TNFα
inhibition of interleukin 1
Inhibit B cells
Block T-cell stimulation
Inhibition of interleukin 6
Inhibition interleukin 17 and 23
43
name a TNF alpha blocker
Etanercept
infliximab
adalimumab
44
how is etanercept given
50mg once per week subcutaneous injection
1-4 weeks for effect
Progressive improvement over 3-6 months
45
describe how etanercept works
- TNF alpha inhibitor
- fusion protein human TNF receptor 2 and Fc human IgG1
- prevents TNF alpha from being able to bind to the TNF alpha receptor on the cells
46
How does Infliximab work
Monoclonal antibody against TNFα
Antibody designed against the mouse binding site of TNFα with remaining 75% human IgG1
47
How do you give infliximab and how long does it take Tok work
3mg/kg Infusions 2-3 hrs in duration 2-6 weeks apart
Days to weeks to have an effect
48
How does adalimumab work
Human TNFα monoclonal antibody
Binds TNFα both soluble and bound (onto the receptor and stops it signalling)
49
How do you give adalimumab and how long for the effects to work
40mg subcutaneously every other week.
Effect seen 1-4 weeks
50
name some IL-1 inhibitors
Anakinra
Canakinumab
Rilonacept
51
How does Anakinra work
Human recombinant IL-1 receptor antagonist
Different from normal IL-1 by addition of N-terminal methionine
Binds IL-1R with same affinity as IL-1
52
How do you give anakinra and how long does it take to have an effect
100mg per day subcutaneous
2-4 weeks to have an effect
53
How is anakinra different from normal IL-1
Different from normal IL-1 by addition of N-terminal methionine
54
How does canakinumab work
Human monoclonal antibody targets IL1β
Approved for some rare autoimmune syndromes
Trials for COPD and gout
55
How do you give Rilonacept
Dimeric fusion protein extracellular domain of IL1R1 and Fc human IgG1
Used more for acute gout
56
How does rituximab work
Chimeric monoclonal antibody against CD20 primarily found on surface of B-cells- binds to the CD20 on the B cell and marks the B cell for destruction
Destroys both normal and malignant B-cells
In combination with methotrexate
57
How do you give rituximab
A single course of 2 infusions of 1000mg given 2 weeks apart depletes B-cells for up to 6 months and possibly 1 year
Effects seen around 3 months after infusions
58
where is CD20
used with macrophages and NK cells are activating the B cell
59
How does Abatacept work
- T cells require stimulation from another dendritic cell
- Fusion protein IgG fused to extracellular domain of CTLA-4 inhibiting its activation
- Prevents 2nd signal (co-stimulatory) from being delivered to T-cell
- Dosage dependent on body weight i.v. infusion over 30mins to 1hr once a month
60
How long does it take for abatacept to work
Response around 3 months
61
how does belatacept work
- Anti CD28
- CD28 is a post stimulatory system which tells the T cells that they should switch on and become activated
- modulates T cell signalling
62
describe the negatives and benefits of abatacept
Benefits
- similar reports of clinical symptom improvement to TNF alpha agents
- fewer adverse effects
negatives
- radiological results are not as good as TNF alpha inhibitors
- slower onset
63
what inhibits IL-6
Tocilizumab
64
Describe how tocilizumab works
Humanized monoclonal antibody against membrane and soluble IL-6 receptor
i.v. 8mg/kg monthly
In combination with methotrexate
- only used if the receptor doest respond to TNF alpha
65
what are iL-17 inhibits used for
Jan 2016 FDA approved secukinumab for moderate to severe psoriasis
- disappointing results for RA
66
name another antibody that can be used in psoriasis
Ustekinumab is an antibody to IL-23 (and IL-12) and can also be used in psoriasis
67
what is the difference between neutralising ADA and non neutralising ADA
Neutralising ADA
- Directly interferes with the biological drugs ability to work
Non-neutralising ADA
- May form immune complexes around injection site reducing drug concentration and pharmacokinetics
- Increased clearance
68
how can you prevent antibody production against biologicals
neutralising ADA and non neutralising ADA
69
what is the downside about biologicals
- eventually after about 15 years the treatment will srtop working or slow down due to antibodies against the monoclonal antibodies
