5 - Rheumatoid Arthritis Treatment

Question 1

TNF-α Effect on Macrophages

Answer 1

Pro-inflammatory cytokines released
Chemokines released

Overall: Increased inflammation

Question 2

TNF-α Effect on Endothelium

Answer 2

Adhesion molecules upregulated
VEGF upregulated

Overall: Increased cell infiltration, increased angiogenesis

Question 3

TNF-α Effect on Hepatocytes

Answer 3

Acute phase response

Overall: Increased CRP in the serum

Question 4

TNF-α Effect on Synoviocytes

Answer 4

Metalloproteinase synthesis increased

Overall: Articular cartilage degradation

Question 5

TNF-α Effect on Osteoclast Progenitors

Answer 5

Increased RANKL expression

Overall: Bone erosions

Question 6

Preventive Treatment

Answer 6

Soluble TNF Receptor
Reduces onset and severity

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

Question 7

Strategies for Inhibiting Cytokines

Answer 7

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

Question 8

How does TNF-α circulate?

Answer 8

As a homotrimer

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

Question 9

Etanercept

Answer 9

Soluble p75 TNF-α receptor

Coupled to the Fc portion of a human IgG1

Question 10

How do we measure response to treatment in RA?

Answer 10

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

Question 11

Methotrexate

Answer 11

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

Question 12

TNF Inhibitors - 5 approved agents

Answer 12

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

Question 13

TNF Inhibitors - Efficacy

Answer 13

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.

Question 14

What makes TNF Inhibitors so exciting?

Answer 14

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%)

Question 15

IL-1

Answer 15

Pro-Inflammatory Cytokine

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

Question 16

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

Answer 16

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.

Question 17

TNF Inhibitors - Downside

Answer 17

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.

Question 18

Anti-TNF-α Agents - Potential Toxicities

Answer 18

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)

Question 19

First line treatment for Rheumatoid Arthritis

Answer 19

Methotrexate (cheaper, almost as effective)

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

Question 20

IL-6

Answer 20

Causes many of the systemic manifestations of inflammation:

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

Question 21

IL-6 is induced by

Answer 21

Monocytes/Macrophages
Endothelial Cells
Mesenchymal Cells, Fibroblasts/Synoviocytes

Question 22

IL-6 Leads to

Answer 22

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)

Question 23

Tocilizumab

Answer 23

Humanized anti-IL-6R monoclonal antibody

Binds either the membrane bound receptor or the soluble receptor (both are necessary for propagation of the signal)

Question 24

Tocilizumab - Efficacy

Answer 24

Improves signs and symptoms of RA at all stages of disease

Question 25

Tocilizumab - Safety

Answer 25

Serious infections
Neutropenia
GI perforations
Liver function test abnormalities
Elevated lipids

Question 26

Abatacept

Answer 26

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

Question 27

Abatacept - Efficacy

Answer 27

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

Question 28

Abatacept - Safety

Answer 28

Risk of re-activation of TB appears low

Does not suppress ability of patients to respond to immunizations

Question 29

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

Answer 29

¯_(ツ)_/¯

Question 30

Drugs targeting B Cells

Answer 30

Rituximab
Ocrelizumab
Ofatumumab

Targets CD20
Kills intermediate-stage B Cells

Question 31

Rituximab

Answer 31

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

Question 32

Rituximab - Safety Issues

Answer 32

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

Question 33

Signal Transduction Targets

Answer 33

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

Question 34

JAK inhibition in RA

Answer 34

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

Question 35

Tofacitinib

Answer 35

Inhibits JAK1 and JAK3

Question 36

Non-biologic FDA approved DMARDs for RA

Answer 36

Methotrexate
Tofacitinib

Hydroxychloroquine
Leflunomide
Sulfasalazine

Question 37

Biologic FDA approved DMARDs for RA

Answer 37

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

Question 38

Rheumatoid Arthritis - Expectations of Treatment

Answer 38

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

Question 39

Rheumatoid Arthritis - Limitations of Treatment

Answer 39

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)