Block E Lecture 3 - Classical DMARDs Flashcards
What are 2 examples of classical DMARDs?
Answers Include:
Sulphasalazine
Methotrexate
Leflunomide
Hydroxychloroquine
How is Sulphasalazine metabolised?
It is converted into mesalazine (the active agent) and sulphapyridine, which is absorbed, metabolised and excreted
(Slide 2)
What is the mechanism of action of sulphasalazine?
It inhibits B cell activity, reducing IgG and rheumatoid factor (RF) production
It also may inhibit the translocation of NF-κB transcription factors to the nucleus, inhibiting cytokine, chemokine, adhesion molecule synthesis and osteoclast formation
(Slide 3)
What are osteoclasts?
Specialized, multinucleated cells which are responsible for breaking down bone tissue
(Slide 3)
What are 3 adverse effects which sulphasalazine can have?
Answers Include:
Skin reactions such as rashes
Gastro-intestinal intolerance
Leukopenia
Neutropenia
Thrombocytopenia
Orange Urine
(Slide 4)
What are leukopenia, neutropenia and thrombocytopenia?
Leukopenia: Low white blood cell count
Neutropenia: Low neutrophil count
Thrombocytopenia: Low platelet count
(Slide 4)
What should be done during the first 3 months of treatment with sulphasalazine?
Blood cell counts should be taken
(Slide 4)
What are the disadvantages of sulphasalazine?
It is not very potent or selective, meaning that you need to use a large concentration of the drug, and there is potential for off-target adverse effects occurring
(Slide 5)
Why is sulphasalazine used despite its disadvantages?
As it is cheap and has manageable side effects, as well as it being able to be used in pregnant women and continued preoperatively (in the lead up to a surgery)
(Slide 5)
What are the mechanisms of action of mexthotrexate?
It inhibits dihydrofolate reductase, inhibiting purine and pyrimidine synthesis and therefore DNA synthesis and cell proliferation, including T- cells, B-cells, osteoclasts and fibroblasts
At low doses, it stimulates the release of adenosine, which has potent anti-inflammatory effects when it acts on A2a and A3 receptors
(Slide 6)
What are the adverse effects of methotrexate?
Side effects which occur from cell proliferation, such as bone marrow depression, blood dyscrasias, infection due to lack of white blood cells etc
(Slide 7)
What are 3 reasons why understanding the mechanism of action of classical DMARDs helps us?
We can develop better drugs which are more specific
We can identify better biomarkers which indicate if the drug is working early in treatment
We can improve personalised medicine using pharmacogenetics
(Slide 8)
What are 4 key cytokines which are used as targets in the treatment of rheumatoid arthritis?
Tumour necrosis factor alpha (TNFα)
IL-1
IL-6
IL-7
(Slide 11)
What are the 2 forms of TNFα?
Membrane-bound and soluble
(Slide 12)
What does TNFα Converting Enzyme (TACE) do?
It cleaves the membrane-bound form of TNFα, releasing the activate soluble form.
(Slide 12)
What does TNFα binding to TNFR-1 and TNFR-2 lead to?
TNFR-1: TNFα binding leads to apoptosis
TNFR-2: TNFα binding leads to recruitment of TRAF2 to the intracellular domain of the receptor.
This eventually leads to the activation of NF-κB transcription factors which translocate to the nucleus and promote transcription of certain pro-inflammatory and proliferative genes
(Slide 13)
What products does the TNFα pathway result in the production of?
TNFα
IL-1β
Upregulation of adhesion molecules (such as ICAM-1, VCAM-1)
Cytokines that further enhance the immune response
Activators of inflammatory pathways (arachidonic acid metabolites, superoxides and nitric oxide)
(Slide 14)
What kind of antibody is infliximab and what does this mean?
It is a chimeric antibody which is 25% mouse derived and 75% human protein
(Slide 15)
What is the mechanism of action of infliximab?
It binds to and neutralises both the soluble and membrane bound TNFα, inhibiting TNFα signalling
(Slide 16)
Other than directly binding to TNFα, what are 2 other mechanisms of action which can be used to reduce TNFα signalling?
- Antibody dependent cell-mediated cytotoxicity (ADCC): Antibodies bind to TNFα expressing cells, such as T cells, marking the cells for destruction by the immune cells, such as natural killer cells or macrophages
- Lysis of TNFα-expressing cells through the complement system: Complement activation can also occur when antibodies bind to TNFα-expressing cells. The complement system tags the cell, signalling phagocytes to engulf and destroy it.
(Slide 17)
What are 2 examples of biological agents used in the treatment of rheumatoid arthritis?
Answers Include:
Infliximab
Etanercept
Golimumab
Certolizumab Pegol
Adalimumab
Anakinra
(Slides 18 and 19)
What are 2 examples of cytokine blocking agents which are used in the treatment of rheumatoid arthritis?
Etanercept
Anakinra
Note: These are also biologics
(Slide 19)
What is etanercept and how does it work?
It is a soluble TNFα receptor which is fused to the Fc domain of a human IgG antibody.
It binds to TNFα in the blood, preventing it from binding to TNF receptors on target cells, limiting TNFα signalling and inflammation
(Slide 19)
What is anakinra and how does it work?
It is a recombinant human IL-1 receptor antagonist
It binds to IL-1 receptors on the surface of cells blocking the action of IL-1α and IL-1β which are pro-inflammatory cytokines, thus reducing inflammation via blocking these
(Slide 19)
How do T-cells lead to the release of pro-inflammatory mediators?
They activate when they recognise antigens presented by antigen presenting cells (APCs), causing them to differentiate and release pro-inflammatory mediators.
These differ depending on the type of T-cell which is differentiated into, and the type of immune response needed.
(Slide 20)
What is abatacept and how does it work?
It is a fusion protein which consists of the extracellular domain of a cytotoxic T-lymphocyte antigen-4 (CTL4) fused to an IgG antibody.
It binds to the CD80 or CD86 ligands on antigen presenting cells (APCs), blocking the interaction between the APC and the T-cell, preventing T-cells from becoming activated and reducing immune response
(Slide 20)
How does rituximab work?
It is a chimeric murine(mouse)-human monoclonal antibody which binds to CD20 receptors on the surface of B cells, marking them for destruction and depleting their numbers.
(Slide 22)
When is rituximab used and is beneficial?
When anti-TNFα therapy has failed
(Slide 22)
What is a side effect of rituximab?
In 30-40% of patients, an infusion reaction occurs, consisting of a headache, fever, rash, hypotension etc…
Note: Don’t think we need to remember the percentage, just that it’s a fairly common occurrence
(Slide 22)
Why has rituximab been designed to target CD20?
As it is expressed exclusively on B cells, making it highly specific and minimising off-target effects
(Slide 23)
What are JAK inhibitors?
A class of targeted synthetic DMARDS (tsDMARDS), which are small molecule inhibitors which target the Janus-kinase (JAK) pathway, responsible for transmitting signals from cytokine receptors on the cell surface to the nucleus, where the cell can initiate changes in gene expression, promoting inflammation
JAK inhibitors block the activity of one or more JAK enzymes, by intracellularly blocking the tyrosine kinase, preventing the activation of the JAK pathway, reducing the production of pro-inflammatory cytokines
(Slide 24)
State an example of a JAK inhibitor which has been approved to treat rheumatoid arthritis. Mention what it inhibitors and what kind of therapy it is used in.
Either:
Tofacitinib - a JAK 1 and 3 inhibitor which also has a small effect on JAK 2. It is used in moderate to serve RA and is either used in monotherapy or in combination therapy with methotrexate
Or:
Baricitinib - a JAK 1 and 2 inhibitor which is administrated either as a monotherapy or in combination with methotrexate
(Slide 26)
