5 - Rheumatoid Arthritis Treatment Flashcards Preview

Rheumatology > 5 - Rheumatoid Arthritis Treatment > Flashcards

Flashcards in 5 - Rheumatoid Arthritis Treatment Deck (39):
1

TNF-α Effect on Macrophages

Pro-inflammatory cytokines released
Chemokines released

Overall: Increased inflammation

2

TNF-α Effect on Endothelium

Adhesion molecules upregulated
VEGF upregulated

Overall: Increased cell infiltration, increased angiogenesis

3

TNF-α Effect on Hepatocytes

Acute phase response

Overall: Increased CRP in the serum

4

TNF-α Effect on Synoviocytes

Metalloproteinase synthesis increased

Overall: Articular cartilage degradation

5

TNF-α Effect on Osteoclast Progenitors

Increased RANKL expression

Overall: Bone erosions

6

Preventive Treatment

Soluble TNF Receptor
Reduces onset and severity

Can't use in humans because we don't catch it early enough to prevent.

7

Strategies for Inhibiting Cytokines

Neutralization via Monoclonal Antibody or Soluble Receptor
Receptor blockade via antagonists
Anti-inflammatory pathway upregulation

8

How does TNF-α circulate?

As a homotrimer
It must bind 2 receptors to activate a signal. 1 is not enough.

9

Etanercept

Soluble p75 TNF-α receptor
Coupled to the Fc portion of a human IgG1

10

How do we measure response to treatment in RA?

20% improvement in both number of joints that are tender, number of swollen joints, and several levels of pain assessments form H&P

11

Methotrexate

Treats Rheumatoid Arthritis but doesn't do it as well as Etanercept. Just been doing longer.

12

TNF Inhibitors - 5 approved agents

Etanercept (Human recombinant receptor/Fc fusion protein)
Infliximab (Monoclonal Antibody)
Adalimumab (Monoclonal Antibody)
Golimumab (Monoclonal Antibody)
Certolizumab pegol (PEGylated humanized Fab fragment)

13

TNF Inhibitors - Efficacy

Comparable for all 5 approved agents
Improve signs and symptoms (joint pain and swelling)
Improve laboratory parameters (ESR and CRP)
Slow or prevent radiographic progression (erosions and joint space narrowing)

Monotherapy with TNF inhibitors modestly more efficacious than methotrexate for slowing radiographic progression

Combination therapy (Anti-TNF + MTX) better than either one alone!

Effective in early and late disease.

14

What makes TNF Inhibitors so exciting?

They are the first "rational" therapy for RA
They are the first biologically based therapy for RA
They are proof of a concept that a single cytokine plays a critical role in RA pathogenesis
They are an alternative to patients who have failed Methotrexate (~50%)

15

IL-1

Pro-Inflammatory Cytokine

Activates monocytes/macrophages (Inflammation)
Induces fibroblast proliferation (Synovial pannus formation)
Activates chondrocytes (Cartilage breakdown)
Activates osteoclasts (Bone Resorption)

16

IL-1 inhibitors (receptor antagonists and traps - rilonacept)

Didn't really prove efficacious.
This means TNF-α actually drives RA, not IL-1!

DID prove efficacious against Still's Disease (systemic onset of JIA), Muckle Wells Syndrome (Autoinflammatory), NOMID (Neonatal-onset multisystem inflammatory disease), Gout

IL-1ra proved effective against the above DESPITE its low affinity and short half life.

This means IL-1 is key to the pathogenesis of those disorders, but is not the driving force in RA.

17

TNF Inhibitors - Downside

TNF-α induces apoptosis
Chronic depletion of TNF-α enhances the risk of reactivation in latent tuberculosis.
Monocytes can't stick to the endothelium, can't enter the granuloma, granuloma dissolves and disease disseminates.

18

Anti-TNF-α Agents - Potential Toxicities

Injection site or infusion reactions
Opportunistic infections (like fungal!)
Demyelinating disease
CHF
Malignancy?! Lymphoma??!! Melanoma?!?!
Inconvenient (SQ or IV administration)
Cost ($30k/yr, compared to MTX which is $1.5k/yr)

19

First line treatment for Rheumatoid Arthritis

Methotrexate (cheaper, almost as effective)

If that doesn't work (which it won't, in half the cases), add a TNF inhibitor in conjunction.

20

IL-6

Causes many of the systemic manifestations of inflammation:

Acute phase response (CRP, ESR)
Anemia (via induction of Hepcidin)
Hypergammaglobulinemia ("Protein gap")
Hypoalbuminemia

21

IL-6 is induced by

Monocytes/Macrophages
Endothelial Cells
Mesenchymal Cells, Fibroblasts/Synoviocytes

22

IL-6 Leads to

T Cell activation
Megakaryocyte maturation (leading to thrombocytosis)
B Cells (leading to autoantibodies and hypergammaglobulinemia)
Osteoclast reactivation (leading to bone resorption)
Hepatocyte activation (leading to increased CRP, ESR and Hepcidin, decreased CYP450 action)

23

Tocilizumab

Humanized anti-IL-6R monoclonal antibody
Binds either the membrane bound receptor or the soluble receptor (both are necessary for propagation of the signal)

24

Tocilizumab - Efficacy

Improves signs and symptoms of RA at all stages of disease

25

Tocilizumab - Safety

Serious infections
Neutropenia
GI perforations
Liver function test abnormalities
Elevated lipids

26

Abatacept

Inhibits T-Cell Activation by interacting with CD80/86 during activation by an APC.
Prevents T-Cell maturation

27

Abatacept - Efficacy

Efficacious:
As monotherapy
In Methotrexate failures
In anti-TNF failures

28

Abatacept - Safety

Risk of re-activation of TB appears low
Does not suppress ability of patients to respond to immunizations

29

Why does Abatacept work, while CD4 targeting doesn't?

¯\_(ツ)_/¯

30

Drugs targeting B Cells

Rituximab
Ocrelizumab
Ofatumumab

Targets CD20
Kills intermediate-stage B Cells

31

Rituximab

Efficacious:
In combination with Methotrexate
When Methotrexate fails
When Anti-TNF fails

Poor efficacy as monotherapy
Only approved for patients who have failed Anti-TNF therapy

32

Rituximab - Safety Issues

Decline in immunoglobulin levels with repeated treatment
Risk of infections
Rare CNS infections (Progressive Multifocal Leukoencephalopathy)

33

Signal Transduction Targets

Jak kinase inhibitor (approved)
Syk kinase inhibitor (ineffective)
p38 kinase inhibitor (ineffective or toxic)

34

JAK inhibition in RA

JAK involved in signalling through the common gamma chain of several cytokine receptors (IL-2,-4,-7,-8,-15,-21)
Receptor binding initiates binding and phosphorylation of JAK-1 and downstream Stat phosphorylation, dimerization, nuclear translocation and signal transduction

Knock out JAK-3, you get a SCID mouse

35

Tofacitinib

Inhibits JAK1 and JAK3

36

Non-biologic FDA approved DMARDs for RA

Methotrexate
Tofacitinib

Hydroxychloroquine
Leflunomide
Sulfasalazine

37

Biologic FDA approved DMARDs for RA

Cytokine Inhibitors:
IL-1 receptor antagonist - not so useful
TNF Inhibitors
IL-6 receptor antagonist
B Cell Depleting Antibody
T Cell Costimulation inhibitor

38

Rheumatoid Arthritis - Expectations of Treatment

Reduce pain, stiffness, fatigue
Improve quality of life
Prevent joint destruction
Maintain full function
Reduce cardiovascular events
Prolong lifespan

39

Rheumatoid Arthritis - Limitations of Treatment

Not curative
No one treatment is highly effective in >50% of patients
Currently we can't predict who will respond to which drug (need biomarkers for personalized medicine)