227. Biologics and Therapeutics

Question 1

New Approach to RA tx

Answer 1

more aggressive tx for earlier stages of disease. Primary target is state of clinical remission or low disease activity

Question 2

Traditional Non-biologic Disease Modifying Agents for RA

Answer 2

1. Hydroxychloroquine: helps in mild joint disease with MTX, no disease modification
2. Sulfasalazine: effective for mild/moderate disease, slows radiographic damage
3. MTX: CORNERSTONE of RA TX: slows radiographic damage!! (not for use in pregnant women)
4. Leflunomide: stops de novo synthesis of pyrimidine (slows cell turnover), good for moderate-severe disease, slows radiographic damage, Teratogenic!

Question 3

RA Pathology (4 key signs)

Answer 3

1. Overgrowth of synoviocytes at bone cartilage interface (pannus)
2. Angiogenesis in deep lining tissue - brings in inflammatory cells
3. Activates osteoclasts to eat into bone (Synovial hyperplasia)
4. Chronic State of bone erosion and inflammatory hypercellularity in synovial fluid

Question 4

Cytokines secreted in RA inflammation

Answer 4

IL-4,6,10: activates B-Cell for positive feedback to activate more T Cells and Plasma cells with autoantibodies

TNFa: activates macrophages to activate osteoclasts

Question 5

Mechanisms of Biologic Response Modifiers

Answer 5

1. Cytokine Neutralization (anti-cytokine mAb, soluble cytokine receptor)
2. Receptor Blockade (anti-receptor mAb, receptor antagonist)
3. Activation of Anti-inflammatory pathways (antiinflammatory cytokine, suppression of inflammatory cytokine)

Question 6

5 types of anti-TNFa biologic therapies

Answer 6

1. Murine (100% Mouse mAb): develops robust response against mAb!
2. Chimeric (25% mouse mAb-only Fab): infliximab, huge improvement, but body develops anti-mAb response
3. Humanized (5-10% mouse mAb-only 3 hypervariable regions of Fab): less antigenic
4. Fully Human (0% mouse): Adalimumab (Humira), minimal mouse anti-mAb response
5. Human Recombinant Receptor/Fc fusion protein: Etanercept - artifical antibody but Fab is TNFa receptor

Question 7

Which anti-TNFa tx to use?

Answer 7

Adalimumab and etanercept both good alone, both BETTER with MTX

Etanercept + MTX not better than just MTX - why MTX is first line mainstay tx!

Question 8

Blockade of IL-6 Signaling

Answer 8

mAb against IL-6 soluble and cellular receptor
Toci and MTX works same as TNFa with MTX
Good for pts who have no results with TNFa-i

Tocilizumab

Question 9

Other biologic therapies (2)

Answer 9

1. Rituximab: anti-CD20 chimeric mAb - induces apoptosis and decreases pre-B and mature B cells = reduce inflammation
2. Abatacept: CTLA4-IgG Fusion protein - binds CD80/86 to prevent T cell activation, good for people who fail TNFa-i’s

Question 10

Biosimilar definition

Answer 10

Biosimilar =/= generic
Biosimilars have identical properties AND identical actions on the body, modifications to protein structure that affect quaternary structure
Should help drop price for RA meds, but isnt :(

Question 11

JAK-STAT blockers

Answer 11

Tofacitinib (Xeljans): blocks JAK3 = blocks cytokine signalling pathway - prevents IL-6 pathway and more
Many types subtypes of JAK-i’s in clinical trials

Question 12

Safety Issues with biologic DMARDs

Answer 12

Serious/Opportunistic Infection (TB)
Malignancy
Heme abnormalities
Auto-antibodies/Lupus like syndrome

Question 13

how do MTX and TNFa-i’s reduce RA mortality?

Answer 13

BY REDUCING CV DISEASE RISK (comorbid condition of RA)