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Locomotor 2 > Treatments for RA > Flashcards

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

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2
Q

what does synovitis of RA affect

A
  • the joint
  • tendon sheaths
  • other body organs such as increased coronary artery disease
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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
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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

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5
Q

What are the two things that you are trying to treat in RA

A
  • pain relief

- modification of disease progression

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6
Q

how do you treat pain relief in RA

A
  • Follow guidelines as for OA
  • Analgesics and NSAIDs
  • COX-2 inhibitors
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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”
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8
Q

What are the two types of DMARDs

A
  • Conventional DMARDs

- “Biologicals”

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9
Q

What does DMARDs stand for

A

Disease modifying anti-rheumatics

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10
Q

what is the adjunct therapy that can be used for modification of disease progression in RA

A

adjunct therapy = oral corticosteroid pulse

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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

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12
Q

What is the gold standard for RA treatment

A

methotrexate

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13
Q

what are the non pharmacological treatment that can be used for RA

A
  • Physiotherapy
  • occupational therapy
  • podiatry
  • therapy (relaxation, stress management, coping)
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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
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15
Q

what is the only autoimmune disease that effects males more than females

A

Anklyisng spondlytisis

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16
Q

why should you not give a DMARD to pregnant women

A
  • Drugs are often toxic and tetragenic
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17
Q

what is the 1st choice drug in RA

A

Methotrexate

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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
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19
Q

How long does methotrexate take to work

A

3-12 weeks before benefit seen

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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

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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
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22
Q

what type of drug is methotrexate

A
  • it is an antimetabolite - prevents the cell from replicating
  • normally given as an anticancer drug
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23
Q

What is sulfasalazine

A
  • Antibiotics

- combines sulfapyridine and salicylate with azo bond

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24
Q

how do you take sulfasalazine

A

Orally

  • Start at 500mg daily
  • Gradually increased over 4 weeks to 1g twice a day
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25
Q

How long does it take sulfasalazine to work

A

12 weeks before benefits are noted

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26
Q

where is sulfasalazine absorbed

A

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
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27
Q

describe the pathway of sulfasalazine

A
  • sulfasalazine is convereted to 5 ASA in the large intestine
  • then it combines its sulfapyrdine and forms N-actetyltransferase 2
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28
Q

What does sulfasalazine usually treat

A
  • treats ulcerative colitis

- also relieves arthritic symptoms

29
Q

describe how sulfasalazine works

A
  • 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
Q

what type of drug is hydroxychloroquine

A

Anti-malarial drug

31
Q

how do you give hydroxychloroquine

A

Oral with or after food

  • Start 400mg daily
  • Reduced to 2-3 times a week
32
Q

How long does it take for the benefits of hydroxychloroquine to work

A

12 weeks for benefit

33
Q

how does hydroxychloroquine work

A
  • 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
Q

What is the negative of hydroxychloroquine and why should you never give it to a person with Psoriasis

A

= can get nasty rash on flexor department

- shouldn’t be given to anyone with a rash that it makes the rash worse

35
Q

describe how lefunomide works

A
  • inhibits pyrimidine biosynthesis by inhibiting dihydroorotate dehydrogenase (DHODH)
  • This blocks DNA and RNA synthesis
36
Q

How should lefunomide be given

A

10-20mg a day

- 1st 3 days higher dose 100mg a day

37
Q

what is the efficacy of lefunomide similar to

A

methotrexate

38
Q

how does D pencillamine work

A

Copper chelator

Thought to decrease immune response and IL1 generation

Preventing maturation of newly synthesised collagen prevents collagen cross linking (prevent fibrosis)

39
Q

what are the side effects of D pencillamine

A

Kidney damage – monitor for proteinuria

40
Q

how often do you give gold salt IM injections

A
  • 50mg

- 4-6 months before effects are seen

41
Q

do DMARDs act broadly

A

yes

42
Q

what type of biologicals can you use to treat RA

A

inhibition of TNFα

inhibition of interleukin 1

Inhibit B cells

Block T-cell stimulation

Inhibition of interleukin 6

Inhibition interleukin 17 and 23

43
Q

name a TNF alpha blocker

A

Etanercept
infliximab
adalimumab

44
Q

how is etanercept given

A

50mg once per week subcutaneous injection

1-4 weeks for effect

Progressive improvement over 3-6 months

45
Q

describe how etanercept works

A
  • 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
Q

How does Infliximab work

A

Monoclonal antibody against TNFα

Antibody designed against the mouse binding site of TNFα with remaining 75% human IgG1

47
Q

How do you give infliximab and how long does it take Tok work

A

3mg/kg Infusions 2-3 hrs in duration 2-6 weeks apart

Days to weeks to have an effect

48
Q

How does adalimumab work

A

Human TNFα monoclonal antibody

Binds TNFα both soluble and bound (onto the receptor and stops it signalling)

49
Q

How do you give adalimumab and how long for the effects to work

A

40mg subcutaneously every other week.

Effect seen 1-4 weeks

50
Q

name some IL-1 inhibitors

A

Anakinra
Canakinumab
Rilonacept

51
Q

How does Anakinra work

A

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
Q

How do you give anakinra and how long does it take to have an effect

A

100mg per day subcutaneous

2-4 weeks to have an effect

53
Q

How is anakinra different from normal IL-1

A

Different from normal IL-1 by addition of N-terminal methionine

54
Q

How does canakinumab work

A

Human monoclonal antibody targets IL1β

Approved for some rare autoimmune syndromes

Trials for COPD and gout

55
Q

How do you give Rilonacept

A

Dimeric fusion protein extracellular domain of IL1R1 and Fc human IgG1

Used more for acute gout

56
Q

How does rituximab work

A

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
Q

How do you give rituximab

A

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
Q

where is CD20

A

used with macrophages and NK cells are activating the B cell

59
Q

How does Abatacept work

A
  • 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
Q

How long does it take for abatacept to work

A

Response around 3 months

61
Q

how does belatacept work

A
  • 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
Q

describe the negatives and benefits of abatacept

A

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
Q

what inhibits IL-6

A

Tocilizumab

64
Q

Describe how tocilizumab works

A

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
Q

what are iL-17 inhibits used for

A

Jan 2016 FDA approved secukinumab for moderate to severe psoriasis

  • disappointing results for RA
66
Q

name another antibody that can be used in psoriasis

A

Ustekinumab is an antibody to IL-23 (and IL-12) and can also be used in psoriasis

67
Q

what is the difference between neutralising ADA and non neutralising ADA

A

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
Q

how can you prevent antibody production against biologicals

A

neutralising ADA and non neutralising ADA

69
Q

what is the downside about biologicals

A
  • eventually after about 15 years the treatment will srtop working or slow down due to antibodies against the monoclonal antibodies

Locomotor 2 (30 decks)

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