Week 2 - Rheumatoid arthritis Flashcards
(25 cards)
Which small joints are usually involved in RA?
Proximal interphalangeal joints and metacarpal joints
Proximal interphalangeal joints are usually spared
What is a feature of the joints usually affected by RA?
High mobility
Which cells do we target in RA treatment, and why?
Target cells like macrophages and lymphocytes because they’re the primary cells involved in inflammatory reactions
Describe the process by which an autoimmune reaction occurs
A tissue antigen is presented to a T cell by an APC cell. This results in T-cells that are reactive to normal tissue, which are activated and undergo clonal expansion.
These then activate macrophages and B cells
Describe how TNF-a interacts with it’s receptors
TNF-a forms into trimers after release from macrophages
A TNF-a of a trimer attaches to one receptor, while a second attaches to another receptor
The physical association between the two receptors causes the receptor response to TNF-a
Which RA drugs target T-cell proliferation and function?
Methotrexate
Leflunomide
Glucocorticoids
What is an eicosanoid?
Prostaglandins, leukotrienes, thromboxanes, lipoxins and other related compounds
Considered local hormones
Often derived from arachidonic acid
How are eicosanoids important in RA?
Lipid mediators generated via AA biosynthetic metabolism play a central role in progression and chronic inflammation associated with RA by mediating proinflammatory actions.
Eicosanoids are involved in mediating vasodilation/vasoconstriction, coagulation, pain and fever
What is the pharmacological mechanism of non-steroidal anti-inflammatory drugs (NSAIDs)?
Inhibition of cyclooxygenase, specifically COX-2 isoform
What is the tissue antigen to Rheumatoid factor?
The Fc region of normal antibodies
What do anti-TNF-a antibodies do, and how are they produced?
Produced by B cells or genetically engineered
MOA - pick up individual TNF-a molcules before they get to the TNF-a receptors
What’s the difference between Infliximab and Adalimumab?
Infliximab has a modified Fab -the variable region on an antibody specific to TNF-a - that has been modified to minimize human antigenicity
Adalimumab is a completely humanized Fab sequence
Which region of an antibody is consistent?
Fc region
What are some consequences of TNF-a inhibition?
Immunosuppression
Increased rate of infections, including those often seen in immunosuppressed individuals
Particular risk for TB dormant
Increased rate of some malignancies
About what cost are biologics per year?
25 grand
What is the action of methotrexate?
Methotrexate is a folic acid mimic
Inhibits dihydrofolate reductase, the enzyme that interconverts tetrahydrofolic acid with folic acid - DHFR cannot tell the difference between M and folic acid, and M cannot be converted to THF –> inhibition, prevents nucleic acid synthesis and therefore clonal expansion of T-lymphocytes involved in RA
Why is methotrexate toxic?
Inhibits nucleic acid synthesis, so affects rapidly dividing cells i.e. lymphocytes (good for RA), but also bone marrow and gut cells
What are some of the common side effects of methotrexate?
Neutropenia, thrombocytopenia, mouth ulcers and GI upsets Teratogenicity Hepatotoxicity Pulmonary fibrosis Renal function issues (renally excreted)
How are treatments for RA determined?
Disease response
Risk-benefit profile
Cost
Describe the typical treatment schedule for RA
- Start with methotrexate or leflunomide
- Typically accompanied by hydroxychloroquine or sulfasalazine, particularly if metho/leflu isn’t quickly effective
- Addition of a biological agent, usually anti TNF-a
- Low dose glucocorticosteroids commonly used in early phases, when trying to bring RA under control
- Cyclooxygenase inhibitors/NSAIDs for anti-inflammatory action
- Non-pharmacological management i.e. protection of joints, management of CVD risk etc
Describe the typical treatment schedule for RA
- Start with methotrexate or leflunomide
- Typically accompanied by hydroxychloroquine or sulfasalazine, particularly if metho/leflu isn’t quickly effective
- Addition of a biological agent, usually anti TNF-a
- Low dose glucocorticosteroids commonly used in early phases, when trying to bring RA under control
- Cyclooxygenase inhibitors/NSAIDs for anti-inflammatory action
- Non-pharmacological management i.e. protection of joints, management of CVD risk etc
Which glucocorticoids are designed on cortisol?
Prednisolone and dexamethasone
Describe the basic mechanism of glucocorticosteroids
Steroid binds to cytosolic glucocorticoid receptor, which translocates to nucleus and binds recognition sequences on promoter regions of responsive genes, stimulating transcription
Causes production of mediator proteins that suppress inflammatory function
Decreases cytokine production, T-cell recruitment and proliferation and antibody production by B-lymphocytes
What does inhibiting prostaglandin production in RA do?
Suppresses inflammatory symptoms but does not alter disease progression
