Week 2 - Rheumatoid arthritis

Question 1

Which small joints are usually involved in RA?

Answer 1

Proximal interphalangeal joints and metacarpal joints

Proximal interphalangeal joints are usually spared

Question 2

What is a feature of the joints usually affected by RA?

Answer 2

High mobility

Question 3

Which cells do we target in RA treatment, and why?

Answer 3

Target cells like macrophages and lymphocytes because they’re the primary cells involved in inflammatory reactions

Question 4

Describe the process by which an autoimmune reaction occurs

Answer 4

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

Question 5

Describe how TNF-a interacts with it’s receptors

Answer 5

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

Question 6

Which RA drugs target T-cell proliferation and function?

Answer 6

Methotrexate
Leflunomide
Glucocorticoids

Question 7

What is an eicosanoid?

Answer 7

Prostaglandins, leukotrienes, thromboxanes, lipoxins and other related compounds
Considered local hormones
Often derived from arachidonic acid

Question 8

How are eicosanoids important in RA?

Answer 8

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

Question 9

What is the pharmacological mechanism of non-steroidal anti-inflammatory drugs (NSAIDs)?

Answer 9

Inhibition of cyclooxygenase, specifically COX-2 isoform

Question 10

What is the tissue antigen to Rheumatoid factor?

Answer 10

The Fc region of normal antibodies

Question 11

What do anti-TNF-a antibodies do, and how are they produced?

Answer 11

Produced by B cells or genetically engineered

MOA - pick up individual TNF-a molcules before they get to the TNF-a receptors

Question 12

What’s the difference between Infliximab and Adalimumab?

Answer 12

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

Question 13

Which region of an antibody is consistent?

Answer 13

Fc region

Question 14

What are some consequences of TNF-a inhibition?

Answer 14

Immunosuppression
Increased rate of infections, including those often seen in immunosuppressed individuals
Particular risk for TB dormant
Increased rate of some malignancies

Question 15

About what cost are biologics per year?

Answer 15

25 grand

Question 16

What is the action of methotrexate?

Answer 16

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

Question 17

Why is methotrexate toxic?

Answer 17

Inhibits nucleic acid synthesis, so affects rapidly dividing cells i.e. lymphocytes (good for RA), but also bone marrow and gut cells

Question 18

What are some of the common side effects of methotrexate?

Answer 18

Neutropenia, thrombocytopenia, mouth ulcers and GI upsets
Teratogenicity
Hepatotoxicity
Pulmonary fibrosis
Renal function issues (renally excreted)

Question 19

How are treatments for RA determined?

Answer 19

Disease response
Risk-benefit profile
Cost

Question 20

Describe the typical treatment schedule for RA

Answer 20

1. Start with methotrexate or leflunomide
2. Typically accompanied by hydroxychloroquine or sulfasalazine, particularly if metho/leflu isn’t quickly effective
3. Addition of a biological agent, usually anti TNF-a
4. Low dose glucocorticosteroids commonly used in early phases, when trying to bring RA under control
5. Cyclooxygenase inhibitors/NSAIDs for anti-inflammatory action
6. Non-pharmacological management i.e. protection of joints, management of CVD risk etc

Question 21

Describe the typical treatment schedule for RA

Answer 21

1. Start with methotrexate or leflunomide
2. Typically accompanied by hydroxychloroquine or sulfasalazine, particularly if metho/leflu isn’t quickly effective
3. Addition of a biological agent, usually anti TNF-a
4. Low dose glucocorticosteroids commonly used in early phases, when trying to bring RA under control
5. Cyclooxygenase inhibitors/NSAIDs for anti-inflammatory action
6. Non-pharmacological management i.e. protection of joints, management of CVD risk etc

Question 22

Which glucocorticoids are designed on cortisol?

Answer 22

Prednisolone and dexamethasone

Question 23

Describe the basic mechanism of glucocorticosteroids

Answer 23

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

Question 24

What does inhibiting prostaglandin production in RA do?

Answer 24

Suppresses inflammatory symptoms but does not alter disease progression

Question 25

How is leflunomide different to methotrexate?

Answer 25

• Blocks dihydrofolate reductase in the pyrimidine synthesis pathway, so is the same in that is antiproliferative
• It has a longer half life and is more teratogenic than methotrexate
• High hepatotoxicity - monitor renal function