Rheumatoid Arthritis Treatment 5 Flashcards
what is methotrexate
- structural analogue of folic acid
- adenosine theory increasingly accepted
- can be extremely effective against RA
- must be monitored properly
what are the patient safety concerns of methotrexate
- can be toxic in high doses
- given weekly
- use folic acid to reduce ADRs
- only use 2.5mg tablets
- patients must have regular blood tests and be counselled on this medicine
what is the role of leflunomide
- inhibits pyrimidine synthesis and T cell proliferation
- inhibits dihydroorotate dehydrogenase
- half life of 2 weeks so should require loading dose
- rarely used
how can immunosuppressives be used in RA
- only azathioprine used in RA usually
- cyclophosphamide, ciclosporin and mycophenalate more associated with severe ADRs compared to azathioprine
what is the mechanism of action of azathioprine
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
describe the metabolism of azathioprine
- 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
what does 6MP stand for
6 mercaptopurine
what does 6MMP stand for
6 methylmercaptopurine
what does 6TGN stand for
6 thioguanine nucleotides
what does TPMT stand for
thiopurine methyltransferase
what is the role of T cell costimulation
- T cell activation sustains synovitis
- activation requires costimulatory signals
- abatacept blocks these costimulatory signals and prevents T cell activation
describe the structure of abatacept
- soluble human recombinant fusion protein
- CTL4/Fc conjugate
- prevents costimulation
- IV but now available as sc
describe the efficacy of abatacept
- comparable to other biologics
- mild infusion related reactions
- low immunogenicity
describe what B cell depletion leads to
- B cells are required for antigen presentation
- this leads to RF and anti CCP autoantibody production
- if reactive B cells can be destroyed, then antigen production can’t take place
describe the structure of rituximab
- chimeric human mouse monoclonal antibody
- targets CD20 receptor on B cells
- IV infusion of 2 doses of 1000mg 14 days apart, repeated every 6 months
describe the efficacy and safety of rituximab
- most studies show better outcome compared to methotrexate monotherapy
- infection rates remain low
- 1 in 25000 risk of progressive multifocal leukoencephalopathy
- no increase in malignancy
describe the role of IL6
- multifunctional cytokine important in RA
- produced by T and B cells
- wide range of effects including inflammation
describe the structure of tocilizumab
- humanised monoclonal antibody which targets iL6
- competitively blocks IL6 from binding to its cell bound receptor
- can be given as a sc injection
describe the efficacy of tocilizumab
- good efficacy
- comparable to other biologics
describe the effects of tumour necrosis factor blocking therapies
- TNFa has been a major target for biologic RA therapies and are first line after DMARD failure
- wide ranging attenuation of inflammatory effects cause profound disease modification
- more effective when combined with methotrexate
describe the efficacy of TNFa antagonists
all agents follow a similar pattern to ACR response
describe the safety of TNFa antagonists
- generally safe but can reactivate latent TB
- must have chest x ray - slight increase in infection rate but not serious
- all are sc injections and patient must be trained to inject
what are the 4 types of certolizumab pegol
- humanised- 8% immunogenicity rate
- monovalent- does not cross link antigens to form large supramolecular complexes
- better tissue penetration - pegylated- improves drug pharmacokinetics and bioavailability
- fragment- minimises potential Fc mediated effects
outline the order of use of bDMARDs
- offer anti-TNFa first
- switch to different anti TNFa or use IL6 (tocilizumab)/ T cell blocker (abatacept)
- B cell depleter- rituximab
what are the 4 known Janus kinases associated with tsDMARDs
- JAK 1
- JAK 2
- JAK 3
- TYK2
what is the role of JAK 3
- restricted to immune system
- is involved in signal transduction of cytokines via signal transducers and activators of transcription
give an example of a novel JAK inhibitor
tofacitinib
describe the mechanism of action of tofacitinib
- inhibits JAK1, JAK2, and JAK3 in vitro with functional cellular specificity fir JAK 1 and JAK3 over JAK2
- directly or indirectly modulates signalling for an important subset of proinflammatory cytokines
what did the trial data for tofacitinib show
tofacitinib has comparable clinical and functional responses to ADA 40mg every other week
