Rheumatoid Arthritis Treatment 5 Flashcards

1
Q

what is methotrexate

A
  1. structural analogue of folic acid
  2. adenosine theory increasingly accepted
  3. can be extremely effective against RA
  4. must be monitored properly
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2
Q

what are the patient safety concerns of methotrexate

A
  1. can be toxic in high doses
  2. given weekly
  3. use folic acid to reduce ADRs
  4. only use 2.5mg tablets
  5. patients must have regular blood tests and be counselled on this medicine
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3
Q

what is the role of leflunomide

A
  1. inhibits pyrimidine synthesis and T cell proliferation
  2. inhibits dihydroorotate dehydrogenase
  3. half life of 2 weeks so should require loading dose
    - rarely used
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4
Q

how can immunosuppressives be used in RA

A
  1. only azathioprine used in RA usually
  2. cyclophosphamide, ciclosporin and mycophenalate more associated with severe ADRs compared to azathioprine
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5
Q

what is the mechanism of action of azathioprine

A

1.interferes with adenine and guanine ribonucleotides
2. cleaved to 6MP
- 6MP becomes inactive 6-MMP, catalysed by TPMT
- if low TPMT, more 6MP is available to form 6TGNs
- when TPMT levels are low, higher levels of 6TGNS are produced and this is associated with greater risk of myelosuppression
3. must measure TPMT activity before starting to ensure correct dose

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6
Q

describe the metabolism of azathioprine

A
  1. 6MP can be converted in the body to active 6TGNs or inactive 6MMP
    - The enzyme responsible for inactivation is TPMT
    - if this enzyme is low, less 6MP is inactivated and more is available to be converted to active 6TGNs
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7
Q

what does 6MP stand for

A

6 mercaptopurine

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8
Q

what does 6MMP stand for

A

6 methylmercaptopurine

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9
Q

what does 6TGN stand for

A

6 thioguanine nucleotides

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10
Q

what does TPMT stand for

A

thiopurine methyltransferase

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11
Q

what is the role of T cell costimulation

A
  1. T cell activation sustains synovitis
  2. activation requires costimulatory signals
  3. abatacept blocks these costimulatory signals and prevents T cell activation
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12
Q

describe the structure of abatacept

A
  1. soluble human recombinant fusion protein
  2. CTL4/Fc conjugate
  3. prevents costimulation
  4. IV but now available as sc
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13
Q

describe the efficacy of abatacept

A
  1. comparable to other biologics
  2. mild infusion related reactions
  3. low immunogenicity
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14
Q

describe what B cell depletion leads to

A
  1. B cells are required for antigen presentation
  2. this leads to RF and anti CCP autoantibody production
  3. if reactive B cells can be destroyed, then antigen production can’t take place
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15
Q

describe the structure of rituximab

A
  1. chimeric human mouse monoclonal antibody
  2. targets CD20 receptor on B cells
  3. IV infusion of 2 doses of 1000mg 14 days apart, repeated every 6 months
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16
Q

describe the efficacy and safety of rituximab

A
  1. most studies show better outcome compared to methotrexate monotherapy
  2. infection rates remain low
  3. 1 in 25000 risk of progressive multifocal leukoencephalopathy
  4. no increase in malignancy
17
Q

describe the role of IL6

A
  1. multifunctional cytokine important in RA
  2. produced by T and B cells
  3. wide range of effects including inflammation
18
Q

describe the structure of tocilizumab

A
  1. humanised monoclonal antibody which targets iL6
  2. competitively blocks IL6 from binding to its cell bound receptor
  3. can be given as a sc injection
19
Q

describe the efficacy of tocilizumab

A
  1. good efficacy
  2. comparable to other biologics
20
Q

describe the effects of tumour necrosis factor blocking therapies

A
  1. TNFa has been a major target for biologic RA therapies and are first line after DMARD failure
  2. wide ranging attenuation of inflammatory effects cause profound disease modification
  3. more effective when combined with methotrexate
21
Q

describe the efficacy of TNFa antagonists

A

all agents follow a similar pattern to ACR response

22
Q

describe the safety of TNFa antagonists

A
  1. generally safe but can reactivate latent TB
    - must have chest x ray
  2. slight increase in infection rate but not serious
  3. all are sc injections and patient must be trained to inject
23
Q

what are the 4 types of certolizumab pegol

A
  1. humanised- 8% immunogenicity rate
  2. monovalent- does not cross link antigens to form large supramolecular complexes
    - better tissue penetration
  3. pegylated- improves drug pharmacokinetics and bioavailability
  4. fragment- minimises potential Fc mediated effects
24
Q

outline the order of use of bDMARDs

A
  1. offer anti-TNFa first
  2. switch to different anti TNFa or use IL6 (tocilizumab)/ T cell blocker (abatacept)
  3. B cell depleter- rituximab
25
Q

what are the 4 known Janus kinases associated with tsDMARDs

A
  1. JAK 1
  2. JAK 2
  3. JAK 3
  4. TYK2
26
Q

what is the role of JAK 3

A
  1. restricted to immune system
  2. is involved in signal transduction of cytokines via signal transducers and activators of transcription
27
Q

give an example of a novel JAK inhibitor

A

tofacitinib

28
Q

describe the mechanism of action of tofacitinib

A
  1. inhibits JAK1, JAK2, and JAK3 in vitro with functional cellular specificity fir JAK 1 and JAK3 over JAK2
  2. directly or indirectly modulates signalling for an important subset of proinflammatory cytokines
29
Q

what did the trial data for tofacitinib show

A

tofacitinib has comparable clinical and functional responses to ADA 40mg every other week