Reginald D Sanders, MD LSU Clinical Pharmacology Drug Therapy of Rheumatoid Arthritis (RA)
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Transcript of Reginald D Sanders, MD LSU Clinical Pharmacology Drug Therapy of Rheumatoid Arthritis (RA)
![Page 1: Reginald D Sanders, MD LSU Clinical Pharmacology Drug Therapy of Rheumatoid Arthritis (RA)](https://reader036.fdocuments.in/reader036/viewer/2022062304/56649f1b5503460f94c30c2a/html5/thumbnails/1.jpg)
Reginald D Sanders, MDReginald D Sanders, MD
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 + (1:2560) antibody to CCP + (>200 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
synovial inflammation
normal abnormal
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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
NSAID’s & Other Drugs
steroids
analgesics
non-selective NSAIDs
COX-2 selective inhibitors
biologic modifiers
methotrexate
Disease-Modifying Drugs
(DMARDs)antimalarials
sulfasalazine
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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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Reginald D Sanders, MDReginald D Sanders, MD
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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Inhibitors of TNF alpha
inhibits TNF alpha activity
etanercept
(Enbrel®)
infliximab (Remicade
®)
adalimumab
(Humira®)
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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®)
S
S
S
S
S
S
S
S
-S-S--S-S--S-S-
extracellular human TNF-receptor p75
monomer
human IgG1 Fc domain
soluble TNF receptor fusion protein
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Soluble TNF receptor binding
synovial cell
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
human IgG1
mouse binding sites
for TNF
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Infliximab binds TNF alpha
TNF alpha
infliximab
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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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Abatacept (Orencia®)
• selective T-cell co-stimulation modulator
• soluble fusion protein (CTLA-4 antigen + Fc of human IgG1)
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Abatacept (Orencia®)
Fusion Protein (CTLA4 + Fc Fragment)
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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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CD28 Costimulation Provides Signal #2
Co-stimulatory modulation
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Co-stimulatory modulation
Without Abatacept With Abatacept
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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?
NSAID
methotrexateleflunomid
e
sulfasalazin
e
antim
alar
ial
com
bin
atio
n
biolog
ics
gold
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RA - choosing a remittive agent
Mild RA hydroxychloroquine sulfasalazine
Moderate RA hydroxychloroquine sulfasalazine
methotrexate
Severe RA
methotrexate azathioprine
leflunomide biologic modifiers
combinations
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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
NSAID
low dose prednisone
methotrexate
biologic
weeks 0-3 weeks 4-16 weeks 17+
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Reginald D Sanders, MDReginald D Sanders, MD
LSU Clinical Pharmacology
Drug Therapy of Rheumatoid
Arthritis