Transcript What Is Rheumatoid Arthritis?

LSU Clinical Pharmacology
Drug Therapy of
Rheumatoid Arthritis (RA)
Reginald D Sanders, MD
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?
Drug therapy of RA
What Is Rheumatoid
Arthritis?
Drug therapy of RA
Case Presentation
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
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
Case presentation
•laboratory studies
 sedimentation rate = 66 mm/hr
 rheumatoid factor + (1:2560)
 antibody to CCP + (>200 units)
•hand X-rays show small, discrete bony
erosions
Case presentation
What does she have?
What do we do?
RA - clinical picture
synovitis
of MCP &
PIP joints
RA - clinical picture
•persistent arthritis
•hands & feet usually involved
•morning stiffness
•rheumatoid factor & antibody to CCP
•sedimentation rate
•extra-articular disease
RA - joint involvement
symmetrical
joint
involvement
RA - essential features
normal
abnormal
synovial inflammation
RA - extra-articular disease
rheumatoid nodule
RA - extra-articular disease
rheumatoid vasculitis
RA - extra-articular disease
rheumatoid (epi)scleritis
RA - severe arthritis
disabling
arthritis
RA - severe arthritis
bone &
joint
damage
(erosions)
RA - severe arthritis
“arthritis
mutilans”
RA - outcome
with inadequate treatment, a significant
number of patients with RA will
experience significant disability due to
joint destruction
Drug therapy of RA
What Drugs Are Available?
Drugs used to treat RA
NSAID’s & Other Drugs
non-selective NSAIDs
COX-2 selective inhibitors
steroids
analgesics
Disease-Modifying
Drugs (DMARDs)
antimalarials
sulfasalazine
methotrexate
biologic modifiers
Traditional DMARDs
•hydroxychloroquine (anti-malarial)
•sulfasalazine
•methotrexate
•leflunomide
Biologic response modifiers
•etanercept (Enbrel®)
•infliximab (Remicade®)
•adalimumab (Humira®)
•anakinra (Kineret®)
•abatacept (Orencia®)
•rituximab (Rituxan®)
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
Antimalarial agents
•main drug - hydroxychloroquine
•excellent safety profile
•minor side effects
•best-known side effect - retinopathy
•mechanism of action unknown
Antimalarial agents
•slow, gradual improvement (8-16
weeks)
•effective in mild-to-moderate RA
•effective in other conditions
•often used in combination therapy
Antimalarial agents - toxicity
•rash
•marrow suppression
•headache, diarrhea
•retinopathy
•transient muscle weakness
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
Sulfasalazine - toxicity
•rash
•abdominal pain
•marrow suppression
•allergic reaction
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)
Methotrexate - toxicity
•hepatic toxicity
•pneumonitis
•bone marrow suppression
•nausea, stomatitis
•“the yucks”
Methotrexate - toxicity
•accelerated rheumatoid nodulosis
RA - extra-articular disease
rheumatoid nodule
Methotrexate - toxicity
•accelerated rheumatoid nodulosis
•susceptibility to infection
•induction of malignant disease
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)
Leflunomide
®
(Arava )
•common side effects
 diarrhea, nausea
 alopecia
 rash, toxic epidermal necrolysis
 hepatic toxicity
•contraindicated in pregnancy
Drug therapy of RA
Biologic Response Modifiers
Reginald D Sanders, MD
Biologic response modifiers
•targeted therapy for rheumatoid
arthritis
•result of better understanding of
disease processes
•parenteral administration (IV or SQ)
•akin to chemotherapy
Cytokines
•mediate immune functions
•produced by activated immune cells
•actions
 enhance immune response
or
 inhibit immune response
•anticytokine therapy in RA?
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
Inhibitors of TNF alpha
etanercept
(Enbrel®)
infliximab
(Remicade®)
adalimumab
(Humira®)
inhibits TNF alpha activity
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
Etanercept (Enbrel®)
soluble TNF receptor fusion protein
-SS-SS-SS S- S
S
S
S
S
S
S
extracellular human
TNF-receptor p75
monomer
human IgG1 Fc domain
Soluble TNF receptor binding
synovial cell
macrophage
Etanercept (Enbrel®)
•low incidence of side effects
•may truly help fatigue
•marked improvement in RA symptoms
•used in combination with methotrexate
Etanercept - side effects
•local injection site reactions
•headache
•increased risk of infections
•increased risk of autoimmune disease?
•increased risk of malignancy?
Infliximab (Remicade®)
chimeric anti-TNF monoclonal antibody
human IgG1
mouse binding
sites for TNF
Infliximab binds TNF alpha
infliximab
TNF alpha
Infliximab
®
(Remicade )
•chimeric monoclonal antibody
•binds to human TNF alpha
•retards erosive disease
•best when used with methotrexate
•intravenous dosing (q 6-8 weeks)
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?
Adalimumab
®
(Humira )
•fully human recombinant anti-TNF alpha
monoclonal antibody
•subcutaneous every 2 weeks
•side effects similar to other TNF
inhibitors
Abatacept
®
(Orencia )
•selective T-cell co-stimulation modulator
•soluble fusion protein (CTLA-4 antigen +
Fc of human IgG1)
Abatacept
®
(Orencia )
Fusion Protein (CTLA4 + Fc Fragment)
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
Co-stimulatory modulation
Antigen Presentation Generates Signal #1
Co-stimulatory modulation
CD28 Costimulation Provides Signal #2
Co-stimulatory modulation
Without Abatacept
With Abatacept
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
Abatacept – adverse events
•infections
•malignancy?
•infusion reactions (headaches, dizziness,
hypertension)
B-cells – role in RA
B-cells – role in RA
Rituximab
®
(Rituxan )
•monoclonal antibody
•B-cell lymphoma therapy
•binds to & depletes C-20+
cells
Rituximab – CD20 targeting
Biologic modifiers
•etanercept
•adalimumab
•infliximab
•abatacept
•rituximab
anti-TNF
anti-TNF
anti-TNF
T-cell directed
B-cell directed
Biologic modifier naming
•etanercept
•abatacept
•adalimumab
•infliximab
•rituximab
cept
cept
mab
mab
mab
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
Erosive RA - risk factors
•female sex
•synovitis resistant to therapy
•positive rheumatoid factor
•high sedimentation rate
•polyarthritis
•elderly onset of disease
RA - new approaches
•earlier use of remittive drugs in
patients at risk for erosive disease
•combination of remittive drugs
RA - new approaches
•earlier use of remittive drugs in
patients at risk for erosive disease
•combination of remittive drugs
•targeted therapy (biologic response
modifiers)
Therapeutic wheel of fortune?
RA - choosing a remittive agent
Mild RA
hydroxychloroquine
sulfasalazine
Moderate RA
hydroxychloroquine
sulfasalazine
methotrexate
Severe RA
methotrexate
azathioprine
leflunomide
biologic modifiers
combinations
Toxicity - NSAIDs vs DMARDs
•lowest toxicity with salsalate
•DMARDs comparable to most toxic
NSAIDs
•hydroxychloroquine very safe DMARD
Drug therapy of RA
Case Presentation
Therapy - current choices
•NSAIDs
•“disease-modifying” anti-rheumatic
drugs
•corticosteroids
•“biologic agents”
•no “cure”, only “control”
•limitations
Case presentation - therapy
NSAID
low dose prednisone
methotrexate
biologic
weeks 0-3
weeks 4-16
weeks 17+
LSU Clinical Pharmacology
Drug Therapy of
Rheumatoid Arthritis
Reginald D Sanders, MD