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LOCO 2 > Treatment Options for RA > Flashcards

Treatment Options for RA Flashcards

1
Q

How many people in the UK have RA?

A

Over 400,000 (1% of UK population)

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2
Q

How many new cases are diagnosed each year?

A

12,000

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3
Q

Apart from the joints, what else does synovitis of RA affect?

A

Tendon sheaths
Increased coronary artery disease
Significant risk of premature mortality

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4
Q

Which joints are commonly affected?

What pattern - symmetrical or asymmetrical?

A

Small joints of hands and feet (MCP and PIP joints)

Symmetrical

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5
Q

How is RA diagnosed?

A

2010 ACR/EULAR criteria - for the target popualtion with at least 1 swollen joint, with no other explanation.

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6
Q

What are the categories for the 2010 ACR/EULAR criteria?

A

The categories are joint involvement (large/small joints and how many), serology (levels of RF and ACPA), acute phase reactants (normal or abnormal CRP and ESR), duration of symptoms (<6 weeks, >6 weeks).
Need > 6/10 for diagnosis.

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7
Q

What does RF stand for?

What does ACPA stand for?

A

Rheumatoid factor

Anti-citrullinated protein antibodies

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8
Q

What is used for pain relief in RA?

A

Follow guidelines as for OA - analgesics and NSAIDs,, COX-2 inhibitors

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9
Q

How is disease progression modified?

A

Disease modifying anti-rheumatic drugs (DMARDs) - conventional DMARDs or “biologicals”

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10
Q

What is used as adjunct therapy in RA?

A

Oral corticosteroid pulse

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11
Q

According to the NICE guidelines, what is the combination therapy treatment for newly diagnosed RA?

A

Combination of DMARDs as first-line treatment as soon as possible (methotrexate and at least one other DMARD plus short term glucocorticoids), ideally within 3 months of the start of persistent symptoms

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12
Q

According to the NICE guidelines, what is the monotherapy treatment for newly diagnosed RA?
When is this used?

A

DMARD monotherapy and concentrate on fast escalation to a clinically effective dose
When combination therapy isn’t appropriate e.g. comorbidities or pregnancy

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13
Q

According to the NICE guidelines, what is the treatment for recent-onset RA?

A

When disease is under control, try to reduce drug doses to levels that maintain disease control

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14
Q

According to the NICE guidelines, what is the treatment for established RA?

A

When disease is stable, reduce DMARD doseages
When starting new drugs, consider decreasing/stopping pre-existing ones
Arrange a prompt review if doses are decreased or stopped

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15
Q

What is the first choice/gold standard drug in RA?

A

Methotrexate

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16
Q

How is Methotrexate given?

A

Orally once a week on the same day (2.5mg tablets, start between 5-10mg a week)
Can also be given by subcut or IM injection

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17
Q

How long does it take for benefits to be seen on Methotrexate?

A

3-12 weeks

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18
Q

What does methotrexate inhibit? What group of patients can’t take it?

A

Folic acid inhibitor (a chemotherapy drug) - pregnant women. It targets proliferating cells.

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19
Q

How does methotrexate get into the cell and stop DNA and RNA production?

A

Uses the reduced folate carrier/transporter to be actively transported in the cell, becomes poly-glutamated (by folylpolyglutamate synthase) to form the active drug to inhibit dihydrofolate reductase, thereby blocking the conversion of dihydrofolate to tetrahydrofolate. As tetrahydrofolate stores are depleted, thymidylate (TMP) synthesis is reduced. This ultimately stops DNA and RNA synthesis (inhibits purine synthesis).

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20
Q

What two enzymes does methotrexate inhibit?

A

Dihydrofolate reductase

Thymidylate synthetase

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21
Q

What are the side effects of methotrexate? (2)

A

Can cause liver problems (damage)

Can affect blood count (anaemia)

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22
Q

What type of drug is Sulfasalazine?

What compounds does it combine?

A

Antibiotic

Combines sulfapyridine and salicylate with azo bond

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23
Q

How is Sulfasalazine administered?

A

Orally - start 500mg daily, gradually increased over 4 weeks to 1g twice a day.

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24
Q

How long before benefit is noted with Sulfasalazine?

A

12 weeks

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25
Q

How does Sulfasalazine work for RA?

A

Mode of action not well understood - it gets concentrated in connective tissue and serous fluids.

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26
Q

Sulfasalazine is not well absorbed across the gut. How much of the parent drug is absorbed?
How is it metabolised?

A

Less than 15%

Metabolised by gut bacteria into 5-ASA and sulfapyridine (better absorbed)

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27
Q

How can Sulfasalazine be used to treat ulcerative collitis and Crohn’s disease? Why does this reduce arthritic symptoms?

A

Sulfasalazine and metabolites stay in lamina propia in the gut and are weak COX inhibitors and inhibit folate-metabolising enzymes. They reduce gut inflammation and dampen down cytokine production.

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28
Q

Hydroxychloroquine - what type of drug is this?

A

Anti-malarial

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29
Q

How is Hydroxychloroquine administered?

A

Oral (with or after food) - start with 400mg daily and then reduced to 2-3 times a week.

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30
Q

How long until benefits are seen with Hydroxychloroquine?

A

12 weeks

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31
Q

How does Hydroxychloroquine work?

A

It accumulates in lysosomes increasing the pH, decreasing protein modifications.
It blocks Toll-like receptor 9 which recognises DNA-containing immune complexes and so decreases activation of dendritic cells.

32
Q

What group of people can’t have Hydroxychloroquine?

A

Those with psoriasitic arthritis (makes psoriasis worse)

33
Q

Leflunomide has an efficacy similar to methotrexate. How does it work?

A

Inhibits pyridimine biosynthesis through inhibiting dihydroorotate dehydrogenase

34
Q

How is Leflunomide given?

A

100mg a day for the first three days, then 10-20mg a day

35
Q

How are gold salts administered?

A

IM Injections once a week (50mg) or orally (not as effective)

36
Q

How long until benefits are seen with gold salts?

A

4-6 months

37
Q

What do TNF and IL-6 cause in RA?

A

Synovial inflammation, destructive changes and systemic inflammation

38
Q

What does IL-1 cause in RA?

A

Destructive changes and systemic inflammation

39
Q

What cells do anti-malarial drugs inhibit?

A

APC

40
Q

What cells do gold salts and sulfasalazine inhibit? (2)

A

APC

T cell

41
Q

What cells do methotrexate and leflunomide inhibit? (2)

A

T cell

B cell

42
Q

What are biologicals?

A

Generated by genetic engineering - targeted to specific immune cell or to a specific cytokine.

43
Q

Give examples of biologicals that inhibit TNF alpha. (3)

A

Etanercept, infliximab, adalimumab

44
Q

Give an example of a biological that inhibits IL-1.

A

Anakinra

45
Q

Give an example of a biological that inhibits B cells.

A

Rituximab

46
Q

Give an example of a biological that blocks T cell stimulation.

A

Abatacept

47
Q

Give an example of a biological that inhibits IL-6.

A

Tocilizumab

48
Q

What is Etanercept?

A

A TNF alpha blocker - fusion protein human TNF receptor 2 and Fc human IgG1. It soaks up the TNF alpha before it can reach the receptors.

49
Q

How is Etanercept administered?

A

50mg once per week by subcut injection

50
Q

How long does Etanercept take to work?

A

1-4 weeks

Progressive improvement over 3-6 months

51
Q

Infliximab - what is it? How does it work?

A

Monoclonal antibody against TNFα (designed against the mouse binding site of TNFα, with remaining 75% human IgG1)

52
Q

How long does Infliximab take to work?

A

Days to weeks

53
Q

How is Infliximab administered?

A

3mg/kg infusions (2-3 hrs in duration, 2-6 weeks apart)

54
Q

Adalimumab - what is it? How does it work?

A

Human TNFα monoclonal antibody - it binds TNFα.

55
Q

How is Adalimumab administered?

A

40mg subcutaneously every other week

56
Q

How long does Adalimumab take to work?

A

1-4 weeks

57
Q

What is Anakinra?

How is it different from normal IL-1?

A

Human recombinant IL-1 receptor antagonist (binds IL-1 receptor with same affinity as IL-1)
Addition of N-terminal methionine

58
Q

How is Anakinra administered?

How long does it take to work?

A

100mg per day (subcut injection)

2-4 weeks

59
Q

What is Canakinumab?

What is it approved for?

A

Human monoclonal antibody - targets IL1β and binds it before it gets to the receptor.
Approved for some rare autoimmune syndromes and there are trials for COPD and gout

60
Q

What is Rilonacept?

What is it used more for?

A

Dimeric fusion protein - extracellular domain of IL1 receptor 1 and Fc human IgG1
Acute gout

61
Q

What is Rituximab?

How does it work?

A

Chimeric monoclonal antibody against CD20 (primarily found on surface of B-cells)
Destroys both normal and malignant B-cells

62
Q

How is Rituximab administered?

How long does it take to work?

A

In combination with methotrexate. A single course of 2 infusions of 1000mg given 2 weeks apart.
3 months after infusions (but depletes B cells for 6-12 months)

63
Q

Who is given Rituximab?

A

Patients who fail to respond to one or more anti-TNFa agents. It has similar results to TNFa agents but reduced radiological efficacy.

64
Q

What is Abatacept?

How does it work?

A

Fusion protein - IgG fused to extracellular domain of CTLA-4
It blocks macrophages so prevents 2nd signal (co-stimulatory) from being delivered to T-cell

65
Q

How long does Abatacept take to work?

A

3 months

66
Q

What is the benefit of Abatacept over TNF alpha blockers?

What are the disadvantages?

A

Fewer adverse events
It has similar results but reduced radiological efficacy
Slower onset

67
Q

How is Abatacept administered?

A

Dosage dependent on body weight

I.V infusion over 30-60 mins once a month

68
Q

How many % of patients on Abatacept reported a 20% improvement in symptoms?

A

50.4%

69
Q

What else modulates T cell signalling? (3)

A

Belatacept
Anti-CD28
Anti-CTLA4

70
Q

Tocilizumab - what is it?

How does it work?

A

Humanized monoclonal antibody against IL-6 receptor

Binds both membrane-bound IL-6R and soluble IL-6R preventing their interaction with IL-6 and associated gp130.

71
Q

How is Tocilizumab administered?

A

I.V. 8mg/kg monthly (in combination with methotrexate)

72
Q

When is Tocilizumab given?

A

When patients fail to respond to TNFa agents

73
Q

What is Ustekinumab? What can it be used for?

A

An antibody to IL-23 (and IL-12)

Psoriasis

74
Q

In Jan 2016 FDA approved secukinumab (monoclonal antibody, binds to IL-17) for…?

A

Moderate to severe psoriasis

75
Q

IL23 is a target for…?

A

Ankylosing spondylitis

76
Q

What is surprisingly effective?

A

Low Dose Naltrexone (opioid receptor antagonist, has anti-inflammatory action)

LOCO 2 (28 decks)

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