Rheumatoid Arthritis Treatment 5

Question 1

what is methotrexate

Answer 1

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

Question 2

what are the patient safety concerns of methotrexate

Answer 2

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

Question 3

what is the role of leflunomide

Answer 3

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

Question 4

how can immunosuppressives be used in RA

Answer 4

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

Question 5

what is the mechanism of action of azathioprine

Answer 5

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

Question 6

describe the metabolism of azathioprine

Answer 6

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

Question 7

what does 6MP stand for

Answer 7

6 mercaptopurine

Question 8

what does 6MMP stand for

Answer 8

6 methylmercaptopurine

Question 9

what does 6TGN stand for

Answer 9

6 thioguanine nucleotides

Question 10

what does TPMT stand for

Answer 10

thiopurine methyltransferase

Question 11

what is the role of T cell costimulation

Answer 11

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

Question 12

describe the structure of abatacept

Answer 12

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

Question 13

describe the efficacy of abatacept

Answer 13

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

Question 14

describe what B cell depletion leads to

Answer 14

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

Question 15

describe the structure of rituximab

Answer 15

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

Question 16

describe the efficacy and safety of rituximab

Answer 16

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

Question 17

describe the role of IL6

Answer 17

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

Question 18

describe the structure of tocilizumab

Answer 18

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

Question 19

describe the efficacy of tocilizumab

Answer 19

1. good efficacy
2. comparable to other biologics

Question 20

describe the effects of tumour necrosis factor blocking therapies

Answer 20

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

Question 21

describe the efficacy of TNFa antagonists

Answer 21

all agents follow a similar pattern to ACR response

Question 22

describe the safety of TNFa antagonists

Answer 22

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

Question 23

what are the 4 types of certolizumab pegol

Answer 23

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

Question 24

outline the order of use of bDMARDs

Answer 24

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

Question 25

what are the 4 known Janus kinases associated with tsDMARDs

Answer 25

1. JAK 1
2. JAK 2
3. JAK 3
4. TYK2

Question 26

what is the role of JAK 3

Answer 26

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

Question 27

give an example of a novel JAK inhibitor

Answer 27

tofacitinib

Question 28

describe the mechanism of action of tofacitinib

Answer 28

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

Question 29

what did the trial data for tofacitinib show

Answer 29

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