Part 11: Rheumatoid Arthritis Flashcards
what is rheumatoid arthritis?
autoimmune disorder where the immune system attacks tissues of articulating joints (knees and hands) resulting in pain, swelling an degradation of joint tissues
what is the goal of RA treatment?
reduce pain and slow the degeneration of joint tissues
inflammation in the joint spaces causes swelling and pain and eventually ____
erosion of bone and cartilage
pharmacologic management of RA includes a variety of analgesic and anti-inflammatory strategies, whcih can be achieved with ____
NSAIDs
why cant you only use NSAIDs to treat RA?
only reducing the production of inflammatory mediators such as prostaglandins does not address the autoimmune issue and joint damage would continue
what is the significance of corticosteroid use in RA?
immunosuppressive, but have a wide range of systemic adverse effects
what are DMARDs?
disease modifying anti-rheumatic drugs, a large class of drugs that reduce joint tissue damage by modulating immune cell processes and reduce inflammation
give 5 examples of DMARDs
methotrexate, abatacept, infliximab, etanercept, tofacitinib
what is the common first choice treatment for RA?
methotrexate
how is methotrexate used in the treatment of RA?
much lower doses than used in cancer, but possible that some inhibition of the purine pathway contributes by reducing proliferation of immune cells ; but most experts suggest the primary action involves AICAR transformylase, which results in lower adenosine levels in the joint space which has anti-inflammatory effects
when methotrexate inhibits AICAR transformylase, what happens?
AICAR levels increase in cells and competes for binding with enzymes that normally metabolize adenosine and ADP during the making of nucleotides, cellualr concentrations of adenosineso that it is secreted from the cell
once excess adenosine is secreted from cells, its is then available to ___
bind to adenosine receptors on the same cell (autocrine) or a different cell (paracrine)
what is the effect of adenosine receptor signalling pathways in RA?
anti-inflammatory actions by reducing proinflammatory signalling by NF-Kappa-B and decreasing the production of mediators such as TNF-alpha causing a reduction of immune cells in joints
what is TNF-alpha?
tumour necrosis factor alpha, an important pro-inflammatory cytokine involved in chemotaxis and potentiating immune responses by enhancing the production of other inflammatory cytokines
studies have also shown that TNF-alpha may have a role in tissue ____ as well as being a sensitizing agent for ___
damage; nociceptors
TNF-alpha has been shown to be elevated in the ___ of RA patients
synovial fluid
what is infliximab?
an anti-TNF a antibody used for RA treatment
what is Etanercept?
a fusion protein containing TNF-a binding region
infliximaba and etanercept are used in RA, but can also be used in other immune disorders such as ____ and ___
IBS and psoriasis
what is the key difference between infliximab and etanercaept?
their structure;
what is the structure of infliximab?
MAB with similar structure to the classic immunoglobulin structure, like endogenous antibodies
structure of etanercept
similar to therapeutic antibody in that it has a specific binding region, the Fc region is similar to a MAB, but the etanercept has an extracellular part of a TNF receptor
what is the function of etanercept having the extracellular bit of a TNF receptor stuck to it?
TNF thinks its binding to its receptor, but bc it isnt, no pro-inflammatory signalling happens
both infliximab and etanercept have selective binding regions for ___, which prevents it from circulating nad binding to its actual receptor that would cause inflammation
TNF-alpha
antigen presenting cells (such as activated macrophages) interact with ____ cells to provide information about a pathogen and activate the cell-mediated response
T cells
in autoimmune diseases such as RA, antigen presenting cells display ___ antigens to T cells
self
special conditions must be met for a self immune reaction, what is one of them?
there must be a second binding interaction between APC and T cell, called a costimulatory signal
t/f a costimulatory signal is required for activation of T cell
t
how does the co-stimulatory signal between the macropahge and T cell occur?
involves binding of the antigen presenting cell CD80 or CD86 proteins with the T cell CD28 protein
what happens if the costimulatory interaction fails to connect?
T cell will not become activated
what is abatacept?
fusion protein with high binding affinity for CD80 and CD86 on antigen presenting cells
how does abatacept work in RA treatment?
binds to CD80 or CD86 on th epresenting cell, preventing the costimulatory interaction, so the T cell cannot be activated and th eimmune response is dampened
t/f abatacept can also bind to APCs that are not involved in RA, so it can cause ADRs
t
t/f one way to treat RA is to modulate cytokine signalling pathways intracellulary
t
cytokine receptors such as IL-2 receptor are enzyme-linked receptors that couple to ____ signalling pathways to increase production of ____ which amplifies the immune response
JAK STAT; cytokines
what is tofacitinib?
small molecule JAK inhibitor that binds intracellulary to prevent activation of JAK STAT inflammatory pathwasy
what is the MOA of tofacitinib?
inhibit JAK STAT, so fewer cytokines are produced, so the recruitment and activation of other immune cells is dampened
t/f tofacitinib has been shown to improve joint pain and other symptoms associated with RA
t
