Pharmacology and Anti-Cytokine Drugs

Question 1

What are the two major cytokines that cause inflammation?

Answer 1

IL-1 and TNF

Question 2

What are the two major cytokines that cause T-cell growth and division?

Answer 2

IL-2

Question 3

What is the major cytokine that cause defense against viruses?

Answer 3

IFN-alpha

Question 4

What is the major cytokine that causes cell-mediated immunity?

Answer 4

IFN-gamma

Question 5

What is the major cytokine that causes chemotaxis to the sites of inflammation and of cells to secondary lymphoid organs?

Answer 5

IL-8

Question 6

What is the major cytokine that causes down-regulation of immune response and regulation of embryonic development?

Answer 6

TGF-Beta

Question 7

What is the major cytokine that causes wound healing and synthesis of ECM?

Answer 7

EGF

Question 8

What is the major cytokine that causes stimulation of hematopoiesis?

Answer 8

GM-CSF

Question 9

What do DMARDs do?

Answer 9

Prevent proliferation of lymphocytes, reduce the inflammatory process

eg: lefluomide and methotrexate

Question 10

What is the target of biologic agents as anti-rheumatic drugs?

Answer 10

TNF-alpha;

IL-1

Question 11

RA: How does etanrecept (enbrel) work?

Answer 11

recombinant fusion protein consisting of 2 soluble p75 TNF receptor moeties linked to Fc portion of human IgG1

binds TNF-alpha with high affinity and neutralizes its biological activity

admin: subcutaneously;
half-life: ~115 hrs;
(as effective as methotrexate; can combine with methotrextate)

Question 12

RA: How does infliximab (Remicade) work?

Answer 12

“Human Constant and Mouse variable part)

chimeric monoclonal antibody to TNF-alpha; Fc region of human IgG and Fab sequences of a mouse anti-TNF-alpha antibody

reduces blood level of TNF-alpha, may dislodge TNF-alpha bound to cells

admin: IV

Question 13

RA: How does adalimumab (Humira) work?

Answer 13

“Humanized Ab”

recombinant human monoclonal Ab to TNF-alpha;
complexes with soluble TNF-alpha and prevents its interaction with p55 and p75 surface receptors

Admin: subcutaneously

Question 14

How do you know a drug is chimeric?

Answer 14

“xi” before -mab

Question 15

How do you know if a drug is humanized?

Answer 15

“um” before -mab

Question 16

Which drug targets IL-1?

Answer 16

anakinra (kineret)

Question 17

What does anakinra do?

Answer 17

blocks the cellular effects of IL-1

it’s a non-glycosylated IL-1Ra (IL-1 Receptor antagonists; endogenous protein)

admin: daily; subcutaneous

Question 18

What is the pathogenesis of RA (rhematoid arthritis)?

Answer 18

1) activation of innate immune system
2) dendritic cells migrate to lymph node
3) present antigen to T cells
4) T cells proliferate and migrate to joint
5) T cells produce pro-inflammatory CYTOKINES
6) activated MACROPHAGES and FIBROBLASTS produce TNF-alpha
7) Further recruitment of immune and inflammatory cells to joint

Question 19

How does CTLA-4 turn off T cell responses?

Answer 19

CTLA-4 is a TM protein on activated T cell that also binds to B7

It gets upregulated after the T cell is activated.

CTLA-4 biding to B7 prevents necessary costimulation effect of B7/CD28 binding, thus shutting down T cell response

Question 20

How does abatacept work?

Answer 20

Costimulatory blockade

like B7 binding of CTLA-4-Ig

Question 21

What drugs can treat Crohn’s disease?

Answer 21

• infliximab

- certolizumab

Question 22

Crohn’s: How does certolizumab (cimzia) work?

Answer 22

PEGylated Fab fragment of humanized TNF-alpha antibody

binds soluble and membrane bound TNF-alpha;

admin: subcutaneously

Question 23

Lupus: what does benlysta do/work?

Answer 23

monoclonal antibody to BAFF/BLSy

Question 24

Wha is BAFF?

Answer 24

B-cell activating factor (B lymphocyte stimulator); key determinant of whether B cell will survive or die during development of tolerance;
member of TNF-alpha family of proteins

Question 25

What is the pathogenesis of Lupus?

Answer 25

With excess BAFF, B cells proliferate and survive, leading to pro-inflammatory autoantibodies, kidney deposition, and complement activation… which causes inflammation and tissue destruction

Question 26

What are contraindications to anti-cytokine therapy?

Answer 26

• active infection
• if TB+, treat latent TB before therapy
• pre-existing demyelinating disorders

Question 27

What cytokine is targeted for psoriasis?

Answer 27

IL-17A (via secukinumab = cosentyx)