Part 11: Rheumatoid Arthritis

Question 1

what is rheumatoid arthritis?

Answer 1

autoimmune disorder where the immune system attacks tissues of articulating joints (knees and hands) resulting in pain, swelling an degradation of joint tissues

Question 2

what is the goal of RA treatment?

Answer 2

reduce pain and slow the degeneration of joint tissues

Question 3

inflammation in the joint spaces causes swelling and pain and eventually ____

Answer 3

erosion of bone and cartilage

Question 4

pharmacologic management of RA includes a variety of analgesic and anti-inflammatory strategies, whcih can be achieved with ____

Answer 4

NSAIDs

Question 5

why cant you only use NSAIDs to treat RA?

Answer 5

only reducing the production of inflammatory mediators such as prostaglandins does not address the autoimmune issue and joint damage would continue

Question 6

what is the significance of corticosteroid use in RA?

Answer 6

immunosuppressive, but have a wide range of systemic adverse effects

Question 7

what are DMARDs?

Answer 7

disease modifying anti-rheumatic drugs, a large class of drugs that reduce joint tissue damage by modulating immune cell processes and reduce inflammation

Question 8

give 5 examples of DMARDs

Answer 8

methotrexate, abatacept, infliximab, etanercept, tofacitinib

Question 9

what is the common first choice treatment for RA?

Answer 9

methotrexate

Question 10

how is methotrexate used in the treatment of RA?

Answer 10

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

Question 11

when methotrexate inhibits AICAR transformylase, what happens?

Answer 11

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

Question 12

once excess adenosine is secreted from cells, its is then available to ___

Answer 12

bind to adenosine receptors on the same cell (autocrine) or a different cell (paracrine)

Question 13

what is the effect of adenosine receptor signalling pathways in RA?

Answer 13

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

Question 14

what is TNF-alpha?

Answer 14

tumour necrosis factor alpha, an important pro-inflammatory cytokine involved in chemotaxis and potentiating immune responses by enhancing the production of other inflammatory cytokines

Question 15

studies have also shown that TNF-alpha may have a role in tissue ____ as well as being a sensitizing agent for ___

Answer 15

damage; nociceptors

Question 16

TNF-alpha has been shown to be elevated in the ___ of RA patients

Answer 16

synovial fluid

Question 17

what is infliximab?

Answer 17

an anti-TNF a antibody used for RA treatment

Question 18

what is Etanercept?

Answer 18

a fusion protein containing TNF-a binding region

Question 19

infliximaba and etanercept are used in RA, but can also be used in other immune disorders such as ____ and ___

Answer 19

IBS and psoriasis

Question 20

what is the key difference between infliximab and etanercaept?

Answer 20

their structure;

Question 21

what is the structure of infliximab?

Answer 21

MAB with similar structure to the classic immunoglobulin structure, like endogenous antibodies

Question 22

structure of etanercept

Answer 22

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

Question 23

what is the function of etanercept having the extracellular bit of a TNF receptor stuck to it?

Answer 23

TNF thinks its binding to its receptor, but bc it isnt, no pro-inflammatory signalling happens

Question 24

both infliximab and etanercept have selective binding regions for ___, which prevents it from circulating nad binding to its actual receptor that would cause inflammation

Answer 24

TNF-alpha

Question 25

antigen presenting cells (such as activated macrophages) interact with ____ cells to provide information about a pathogen and activate the cell-mediated response

Answer 25

T cells

Question 26

in autoimmune diseases such as RA, antigen presenting cells display ___ antigens to T cells

Answer 26

self

Question 27

special conditions must be met for a self immune reaction, what is one of them?

Answer 27

there must be a second binding interaction between APC and T cell, called a costimulatory signal

Question 28

t/f a costimulatory signal is required for activation of T cell

Answer 28

t

Question 29

how does the co-stimulatory signal between the macropahge and T cell occur?

Answer 29

involves binding of the antigen presenting cell CD80 or CD86 proteins with the T cell CD28 protein

Question 30

what happens if the costimulatory interaction fails to connect?

Answer 30

T cell will not become activated

Question 31

what is abatacept?

Answer 31

fusion protein with high binding affinity for CD80 and CD86 on antigen presenting cells

Question 32

how does abatacept work in RA treatment?

Answer 32

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

Question 33

t/f abatacept can also bind to APCs that are not involved in RA, so it can cause ADRs

Answer 33

t

Question 34

t/f one way to treat RA is to modulate cytokine signalling pathways intracellulary

Answer 34

t

Question 35

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

Answer 35

JAK STAT; cytokines

Question 36

what is tofacitinib?

Answer 36

small molecule JAK inhibitor that binds intracellulary to prevent activation of JAK STAT inflammatory pathwasy

Question 37

what is the MOA of tofacitinib?

Answer 37

inhibit JAK STAT, so fewer cytokines are produced, so the recruitment and activation of other immune cells is dampened

Question 38

t/f tofacitinib has been shown to improve joint pain and other symptoms associated with RA

Answer 38

t