LSU Clinical Pharmacology

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LSU Clinical Pharmacology

• Drug Therapy of Rheumatoid Arthritis (RA)

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Drug therapy of RA - overview

• what is rheumatoid arthritis (RA)?
• what happens to patients with RA?
• what drugs are available?
• how are those drugs used?
• where are we going with therapy?

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Drug therapy of RA
What Is Rheumatoid Arthritis?
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Drug therapy of RA
Case Presentation
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Case presentation

• 25 years old dental hygienist
• 6 months history of pain swelling in the MCP
  PIP joints of both hands
• recent onset swelling in knees, wrists, elbows
  ankles
• very stiff for 2 hours in the morning
• very stiff after sitting

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Case presentation

• pain present daily but varies day to day
• hurts when weather changes abruptly
• with worsening pain, is missing work
• exam shows multiple swollen joints
• incomplete fist formation bilaterally
• small olecranon nodules

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Case presentation

• laboratory studies
• sedimentation rate 66 mm/hr
• rheumatoid factor (12560)
• antibody to CCP (gt200 units)
• hand X-rays show small, discrete bony erosions

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Case presentation

• What does she have?
• What do we do?

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RA - clinical picture
synovitis of MCP PIP joints
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RA - clinical picture

• persistent arthritis
• hands feet usually involved
• morning stiffness
• rheumatoid factor antibody to CCP
• sedimentation rate
• extra-articular disease

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RA - joint involvement
symmetrical joint involvement
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RA - essential features
normal
abnormal
synovial inflammation
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RA - extra-articular disease
rheumatoid nodule
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RA - extra-articular disease
rheumatoid vasculitis
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RA - extra-articular disease
rheumatoid (epi)scleritis
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RA - severe arthritis
disabling arthritis
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RA - severe arthritis
bone joint damage (erosions)
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RA - severe arthritis
arthritis mutilans
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RA - outcome

• with inadequate treatment, a significant number
  of patients with RA will experience significant
  disability due to joint destruction

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Drug therapy of RA
What Drugs Are Available?
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Drugs used to treat RA
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Traditional DMARDs

• hydroxychloroquine (anti-malarial)
• sulfasalazine
• methotrexate
• leflunomide

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Biologic response modifiers

• etanercept (Enbrel)
• infliximab (Remicade)
• adalimumab (Humira)
• anakinra (Kineret)
• abatacept (Orencia)
• rituximab (Rituxan)

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DMARDs - characteristics

• no direct analgesic effect
• no direct anti-inflammatory effect
• delayed onset of benefits
• narrow range of effectiveness
• unique adverse effect profiles
• able to prevent progression of RA

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Antimalarial agents

• main drug - hydroxychloroquine
• excellent safety profile
• minor side effects
• best-known side effect - retinopathy
• mechanism of action unknown

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Antimalarial agents

• slow, gradual improvement (8-16 weeks)
• effective in mild-to-moderate RA
• effective in other conditions
• often used in combination therapy

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Antimalarial agents - toxicity

• rash
• marrow suppression
• headache, diarrhea
• retinopathy
• transient muscle weakness

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Sulfasalazine

• useful in mild-to-moderate RA
• side effects frequent, but usually mild
• alternative to hydroxychloroquine
• usually takes 8-16 weeks to begin working
• mechanism of action unknown

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Sulfasalazine - toxicity

• rash
• abdominal pain
• marrow suppression
• allergic reaction

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Methotrexate

• most widely used remittive agent for RA
• advantages
• disadvantages
• favored drug for severe RA
• mechanism of action in RA unknown (inhibits folic
  acid metabolism)

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Methotrexate - toxicity

• hepatic toxicity
• pneumonitis
• bone marrow suppression
• nausea, stomatitis
• the yucks

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Methotrexate - toxicity

• accelerated rheumatoid nodulosis

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RA - extra-articular disease
rheumatoid nodule
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Methotrexate - toxicity

• accelerated rheumatoid nodulosis
• susceptibility to infection
• induction of malignant disease

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Leflunomide (Arava)

• immunomodulatory drug
• inhibits pyrimidine synthesis
• retards progression of RA erosions
• loading dose first three days (100 mg)
• once daily therapy thereafter (20 mg)

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Leflunomide (Arava)

• common side effects
• diarrhea, nausea
• alopecia
• rash, toxic epidermal necrolysis
• hepatic toxicity
• contraindicated in pregnancy

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Drug therapy of RA

• Biologic Response Modifiers

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Biologic response modifiers

• targeted therapy for rheumatoid arthritis
• result of better understanding of disease
  processes
• parenteral administration (IV or SQ)
• akin to chemotherapy

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Cytokines

• mediate immune functions
• produced by activated immune cells
• actions
• enhance immune response or
• inhibit immune response
• anticytokine therapy in RA?

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Tumor necrosis factor alpha

• produced by macrophages (cytokine)
• stimulates synovial cells to produce collagenases
• found in increased amounts in RA synovium
• must attach to cell receptor to work

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TNF inhibition - approaches

• cell surface receptor antagonists
• soluble receptor antagonists
• antibodies to cytokines
• antibodies to cytokine receptors

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Inhibitors of TNF alpha
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Etanercept (Enbrel)

• biologic modifier
• recombinant human tumor necrosis factor receptor
  fusion protein
• binds inactivates soluble TNF
• subcutaneously, once or twice a week
• retards erosive disease

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Etanercept (Enbrel)
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Soluble TNF receptor binding
macrophage
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Etanercept (Enbrel)

• low incidence of side effects
• may truly help fatigue
• marked improvement in RA symptoms
• used in combination with methotrexate

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Etanercept - side effects

• local injection site reactions
• headache
• increased risk of infections
• increased risk of autoimmune disease?
• increased risk of malignancy?

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Infliximab (Remicade)
chimeric anti-TNF monoclonal antibody
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Infliximab binds TNF alpha
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Infliximab (Remicade)

• chimeric monoclonal antibody
• binds to human TNF alpha
• retards erosive disease
• best when used with methotrexate
• intravenous dosing (q 6-8 weeks)

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Infliximab - side effects

• activation of latent tuberculosis
• activation of latent histoplasmosis
• increased risk of other infections
• increased risk of demyelinating disease?
• increased risk of malignancy?

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Adalimumab (Humira)

• fully human recombinant anti-TNF alpha monoclonal
  antibody
• subcutaneous every 2 weeks
• side effects similar to other TNF inhibitors

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TNF inhibition - approaches

• cell surface receptor antagonists
• soluble receptor antagonists
• antibodies to cytokines
• antibodies to cytokine receptors

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T-cells role in RA

• large number T cells in RA joints
• T cells from RA joints can transfer disease to
  immunodeficient mice
• depletion of pathogenic T cells prevent
  collagen-induced arthritis in mice

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Activated T-cells role in RA

• release chemical mediators that stimulate
  activity of other immune cells
• other immune cells release second set of
  mediators that induce inflammation joint damage

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Abatacept (Orencia)

• selective T-cell co-stimulation modulator
• soluble fusion protein (CTLA-4 antigen Fc of
  human IgG1)

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Abatacept (Orencia)
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Abatacept (Orencia)

• selective T-cell co-stimulation modulator
• soluble fusion protein (CTLA-4 antigen Fc of
  human IgG1)
• binds to CD80 CD86
• blocks interaction with CD28
• attenuates T-cell activation

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Co-stimulatory modulation
Antigen Presentation Generates Signal 1
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Co-stimulatory modulation
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Co-stimulatory modulation
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Abatacept - indications

• reduce signs symptoms of RA
• slow progression of structural damage
• improve physical function
• used if inadequate response to methotrexate
  and/or TNF inhibitors
• not used with TNF inhibitors

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Abatacept adverse events

• infections
• malignancy?
• infusion reactions (headaches, dizziness,
  hypertension)

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B-cells role in RA
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B-cells role in RA
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Rituximab (Rituxan)

• monoclonal antibody
• B-cell lymphoma therapy
• binds to depletes C-20 cells

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Rituximab CD20 targeting
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Biologic modifiers

• etanercept anti-TNF
• adalimumab anti-TNF
• infliximab anti-TNF
• abatacept T-cell directed
• rituximab B-cell directed

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Biologic modifier naming

• etanercept cept
• abatacept cept
• adalimumab mab
• infliximab mab
• rituximab mab

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RA changing approaches

• earlier use of remittive drugs in patients at
  risk for erosive disease
• majority of joint damage within 5 years
• typical patient has severe functional impairment
  within 2 years
• at 10 years 40 of patients disabled

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Erosive RA - risk factors

• female sex
• synovitis resistant to therapy
• positive rheumatoid factor
• high sedimentation rate
• polyarthritis
• elderly onset of disease

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RA - new approaches

• earlier use of remittive drugs in patients at
  risk for erosive disease
• combination of remittive drugs

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RA - new approaches

• earlier use of remittive drugs in patients at
  risk for erosive disease
• combination of remittive drugs
• targeted therapy (biologic response modifiers)

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Therapeutic wheel of fortune?
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RA - choosing a remittive agent
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Toxicity - NSAIDs vs DMARDs

• lowest toxicity with salsalate
• DMARDs comparable to most toxic NSAIDs
• hydroxychloroquine very safe DMARD

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Drug therapy of RA
Case Presentation
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Therapy - current choices

• NSAIDs
• disease-modifying anti-rheumatic drugs
• corticosteroids
• biologic agents
• no cure, only control
• limitations

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Case presentation - therapy
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LSU Clinical Pharmacology

• Drug Therapy of Rheumatoid Arthritis