Reginald D Sanders, MD LSU Clinical Pharmacology Drug Therapy of Rheumatoid Arthritis (RA)

Reginald D Sanders, MDReginald D Sanders, MD

LSU Clinical Pharmacology

Drug Therapy of Rheumatoid Arthritis

(RA)

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

synovial inflammation

normal abnormal

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

steroids

analgesics

non-selective NSAIDs

COX-2 selective inhibitors

biologic modifiers

methotrexate

Disease-Modifying Drugs

(DMARDs)antimalarials

sulfasalazine

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

Reginald D Sanders, MDReginald D Sanders, MD

Drug therapy of RA

Biologic Response Modifiers

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

inhibits TNF alpha activity

etanercept

(Enbrel®)

infliximab (Remicade

®)

adalimumab

(Humira®)

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®)

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

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

TNF alpha

infliximab

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

CD28 Costimulation Provides Signal #2

Co-stimulatory modulation

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

Biologic modifier naming

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

NSAID

methotrexateleflunomid

e

sulfasalazin

e

antim

alar

ial

com

bin

atio

n

biolog

ics

gold

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+

Reginald D Sanders, MDReginald D Sanders, MD

LSU Clinical Pharmacology

Drug Therapy of Rheumatoid

Arthritis