5 - Rheumatoid Arthritis Treatment Flashcards
TNF-α Effect on Macrophages
Pro-inflammatory cytokines released
Chemokines released
Overall: Increased inflammation
TNF-α Effect on Endothelium
Adhesion molecules upregulated
VEGF upregulated
Overall: Increased cell infiltration, increased angiogenesis
TNF-α Effect on Hepatocytes
Acute phase response
Overall: Increased CRP in the serum
TNF-α Effect on Synoviocytes
Metalloproteinase synthesis increased
Overall: Articular cartilage degradation
TNF-α Effect on Osteoclast Progenitors
Increased RANKL expression
Overall: Bone erosions
Preventive Treatment
Soluble TNF Receptor
Reduces onset and severity
Can’t use in humans because we don’t catch it early enough to prevent.
Strategies for Inhibiting Cytokines
Neutralization via Monoclonal Antibody or Soluble Receptor
Receptor blockade via antagonists
Anti-inflammatory pathway upregulation
How does TNF-α circulate?
As a homotrimer
It must bind 2 receptors to activate a signal. 1 is not enough.
Etanercept
Soluble p75 TNF-α receptor
Coupled to the Fc portion of a human IgG1
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
Methotrexate
Treats Rheumatoid Arthritis but doesn’t do it as well as Etanercept. Just been doing longer.
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)
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.
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%)
IL-1
Pro-Inflammatory Cytokine
Activates monocytes/macrophages (Inflammation)
Induces fibroblast proliferation (Synovial pannus formation)
Activates chondrocytes (Cartilage breakdown)
Activates osteoclasts (Bone Resorption)
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.
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.
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)
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.
IL-6
Causes many of the systemic manifestations of inflammation:
Acute phase response (CRP, ESR)
Anemia (via induction of Hepcidin)
Hypergammaglobulinemia (“Protein gap”)
Hypoalbuminemia
IL-6 is induced by
Monocytes/Macrophages
Endothelial Cells
Mesenchymal Cells, Fibroblasts/Synoviocytes
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)
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)
Tocilizumab - Efficacy
Improves signs and symptoms of RA at all stages of disease
Tocilizumab - Safety
Serious infections Neutropenia GI perforations Liver function test abnormalities Elevated lipids
Abatacept
Inhibits T-Cell Activation by interacting with CD80/86 during activation by an APC.
Prevents T-Cell maturation
Abatacept - Efficacy
Efficacious:
As monotherapy
In Methotrexate failures
In anti-TNF failures
Abatacept - Safety
Risk of re-activation of TB appears low
Does not suppress ability of patients to respond to immunizations
Why does Abatacept work, while CD4 targeting doesn’t?
¯_(ツ)_/¯
Drugs targeting B Cells
Rituximab
Ocrelizumab
Ofatumumab
Targets CD20
Kills intermediate-stage B Cells
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
Rituximab - Safety Issues
Decline in immunoglobulin levels with repeated treatment
Risk of infections
Rare CNS infections (Progressive Multifocal Leukoencephalopathy)
Signal Transduction Targets
Jak kinase inhibitor (approved)
Syk kinase inhibitor (ineffective)
p38 kinase inhibitor (ineffective or toxic)
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
Tofacitinib
Inhibits JAK1 and JAK3
Non-biologic FDA approved DMARDs for RA
Methotrexate
Tofacitinib
Hydroxychloroquine
Leflunomide
Sulfasalazine
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
Rheumatoid Arthritis - Expectations of Treatment
Reduce pain, stiffness, fatigue Improve quality of life Prevent joint destruction Maintain full function Reduce cardiovascular events Prolong lifespan
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)
