living with rheumatoid arthritis: understanding options, understanding goals eric ruderman, m.d....
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Living with Rheumatoid Arthritis:
Understanding Options, Understanding Goals
Eric Ruderman, M.D.Professor of Medicine, Rheumatology
Northwestern University Feinberg School of Medicine
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The Burden of Rheumatoid Arthritis
• Systemic inflammatory disease1
• Autoimmune etiology1
• Affects 2 million people in the United States1
– Age of onset 30-60 years
• Lifetime cost approaches that of cardiovascular diseases2
• Associated with an increased mortality risk3
1. Arthritis Foundation. At: http://www.arthritis.org/conditions/diseasecenter/RA/default.asp. Accessed June 4, 2007.2. Kvien. Pharmacoeconomics. 2004;22(suppl 2):1.3. Gabriel et al. Arthritis Rheum. 2003;48:54.
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Clinical Course of RA
• Chronic and progressive disease
• 50% of patients have irreversible joint damage at 2 years– The true cause of late disability
• If not treated early and aggressively, RA leads to– Increasing joint destruction and deformity– Progressive physical disability– Reduced QOL
Doran et al. Arthritis Rheum. 2002;46:625; Hulsmans et al. Arthritis Rheum. 2000;43:1927; Marra. Am J Health Syst Pharm. 2006;63:S4.
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Images courtesy of J. Cush, 2005.
The Clinical Spectrum of RA
Active with some deformity
Early PIP swelling Late-stage deformities
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Adapted from Kirwan JR. J Rheumatol. 2001;28:881-886.
Inflammation and subsequent radiographic progression are dominant contributors to disability in RA patients
• Effect of joint destruction dominates disability late in disease• Inflammatory joint symptoms determine disability early in disease
0 5 10 15 20 25 30
Disability
Inflammation
Joint damage
Years of disease
Sev
erit
y (a
rbit
rary
u
nit
s)
Progression of RA
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New ACR/EULAR RA criteria
RA is classified or diagnosed with a
score ≥6
Aletaha D, et al. EULAR 2010, Rome, Plenary session
JOINT DISTRIBUTION
1 Large Joint 0
2-10 Large Joints 1
1-3 Small Joints (large jts excluded) 2
4-10 Small Joints (large jts excluded) 3
>10 Joints (at least 1 small joint) 5
SEROLOGY
Negative RF and Negative ACPA 0
Low Positive RF or ACPA (≤3x ULN) 2
High Positive RF or ACPA (>3x ULN) 3
SYMPTOM DURATION
<6 weeks 0
≥6 weeks 1
ACUTE PHASE REACTANTS
Normal CRP and ESR 0
Abnormal CRP or ESR 1
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Inflammatory Arthritis - Clues
Inflammatory Osteoarthritis
Mode of onset Subacute Insideous
Diurnal variation AM worst PMworst
AM stiffness > 45 minutes < 15 minutes
Effect of activity better worse
Systemic symptoms
Yes No
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Bykerk VP, et al. J Musculoskelet Med. 2004;21:133-146.O’Dell JR. N Engl J Med. 2004;350:2591-2602.Bingham CO, et al. J Fam Pract. 2007;59(suppl 10):S1-S8.
DMARD Benefits Considerations
Hydroxychloroquine• Effective for mild disease and in
combination with methotrexate
• Takes 3-6 months to become effective
• No evidence of halting radiographic progression
Sulfasalazine
• Effective for mild-to-moderate disease• May be used in combination with other
agents• Slows radiographic damage
• Contraindicated in patients who have sulfa allergies
Methotrexate
• Cornerstone of most treatment regimens for RA
• Well-tolerated once-weekly medication• Slows radiographic damage
• Contraindicated in potentially childbearing women
• Usually administered with folic acid supplementation
Leflunomide• For moderate-to-severe disease• Slows radiographic progression
• Greater cost• Long half-life• Contraindicated in
potentially childbearing women
Traditional Non-Biologic DMARDs
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NORMALRHEUMATOID ARTHRITIS
Synovial membrane
Cartilage
CapsuleSynovial fluid
Inflamed synovial
membrane
Pannus
Major cell types: T lymphocytes Macrophages
Minor cell types: Fibroblasts Plasma cells Endothelium Dendritic cells
Major cell type: Neutrophils
Cartilage Thinning
The Pathogenesis of RA
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Pathophysiology of RAEarly Established
Capsule
Synovialmembrane
Synoviocytes Cartilage
Plasmacell
Bone erosion Pannus
Neutrophils
Normal Joint RA
Synoviocyte accumulation
Angiogenesis
Dendritic cell
Neutrophils
T cells B cells
Adapted with permission from Choy and Panayi. N Engl J Med. 2001;344:907. Copyright © 2001 Massachusetts Medical Society. All rights reserved.
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Bone Damage in RA
Generalized skeletal osteoporosis
Periarticular osteoporosis
Bone erosion
Goldring. Curr Opin Rheumatol. 2002;14:406.The Association of the British Pharmaceutical Industry. At:http://www.abpi.org.uk/publications/publication_details/targetArthritis/images/pg4_146.gif
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Most RA Patients Develop Bone Erosions During First 2 Years of Disease
Patients with RA <1 year underwent annual radiologic assessment of hands and feet.Hulsmans et al. Arthritis Rheum. 2000;43:1927.
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Therapeutic Aim in RA
• Joint damage– Retardation– Prevention– Reversal
• Requires a comprehensive approach– Type of intervention– Timing– Follow-up management– Assessment of comorbid
conditions
• Signs and symptoms– Improvement
– Remission
• Disability– Improvement– Prevention– Reversal
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Global RA Management Goals
• Prevent or control joint damage
• Prevent loss of function
• Decrease pain
• Treat comorbidities along with RA
• Improve functional status
Tutuncu Z, et al. Rheum Dis Clin North Am. 2007;33:57-70.
The ideal objective: disease remission
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The Traditional Treatment Pyramid for RA: Sequential Drug Therapy
Adapted from Primer on Rheumatic Diseases. 10th ed. The Arthritis Foundation; 1993.
Methotrexate, azathioprine, penicillamine
Antimalarials, gold, sulfasalazine
Surgery Corticosteroids for flares
AnalgesicsIntra-articular
steroids
Experimental drugs,
Biologics
Salicylates or other NSAIDs
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Expert Panel Algorithm for Treating RA to Target • Primary target in treating RA now defined as a state of
clinical remission– Low disease activity (LDA) may be an alternative therapeutic goal
to remission, particularly in established long-standing disease
Maintarget
ActiveRA
RemissionSustainedremission
Alter-nativetarget
Low diseaseactivity
Sustained lowdisease activity
Adapt therapyif state is lost
Adapt therapyif state is lost
Adapt therapyaccording to
disease activity
Adapt therapyaccording to
disease activity
Assessdisease activity about
every 3-6 months
Use a composite measureof disease activityevery 1-3 months
Smolen et al. Ann Rheum Dis 2010;69:631–637.
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Rheumatoid Arthritis: Where Are We Now With Treatment?• Nonbiologic DMARDs
– Monotherapy• MTX• SSZ• Leflunomide• Hydroxychloroquine
– Combination therapy• Dual therapy • Triple therapy
• Glucocorticoids– Local– Systemic
• Combined with DMARDs
• Biologic DMARDs– TNF antagonists
• Adalimumab• Certolizumab• Etanercept• Golimumab• Infliximab
– IL-6 antagonist• Tocilizumab
– IL-1 antagonist• Anakinra
– Costimulation modulator• Abatacept
– B-cell depletion• Rituximab
• Emerging targets– Kinase inhibitors - Tofacitinib
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ActivatedActivatedMacrophageMacrophage
TargetTargetCellCell
SignalSignal
sTNFR
sTNFR
TNFTNF
TACETACE
TACETACE
TNF and TNF Receptors
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Mouse HumanCDR=Complementarity–determining regionPEG=Polyethylene glycol
Chimeric monoclonal antibody
CDR
InfliximabIgG1
Human recombinant antibodies
AdalimumabIgG1
Humanized Fab’ fragment
EtanerceptIgG1
Human recombinant receptor/Fc fusion protein
Fc
Receptor
Constant 2
Constant 3
PEGPEG PEGPEG
CertolizumabCertolizumab
VLVL VHVH
CLCL
CH1CH1
GolimumabIgG1
Adapted from Tracey D et al. Pharmacol Ther. 2008;117:244-279
Structures of TNF-α Inhibitors
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ActivatedActivatedmacrophagemacrophage
TargetTargetcellcell
TNFTNF
p55p55
p75p75
anti-TNF Abanti-TNF Ab
TNF Inhibition: Monoclonal Antibodies
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Transiently depletes Transiently depletes pre-B and mature B pre-B and mature B cells onlycells only
Progenitor and plasma Progenitor and plasma cells not affectedcells not affected
Targeting B Cells: Rituximab -A Chimeric Anti-CD20 Monoclonal Antibody
Antigen
B
Rituximab
Antibodies
CD20
Edwards and Cambridge. Rheumatology (Oxford). 2001;40:205; Edwards et al. N Engl J Med. 2004;350:2572;Johnson and Glennie. Semin Oncol. 2003;30(suppl 2):3; Shanahan et al. Curr Opin Rheumatol. 2003;15:226; Silverman and Weisman. Arthritis Rheum. 2003;48:1484.
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Targeting T Cells: Abatacept—a Human Immunoglobulin Receptor Fusion Protein
With AbataceptWithout Abatacept
Abatacept(CTLA4Ig)Activated
T cell
DC T
CD28CD80/86
DCT
• Competes for CD28 binding to CD80/86
• Attenuate T-cell–mediated autoimmunity
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1. Leonard WJ. Nat Rev Immunol. 2001;1(3):200-208; 2. Mavers M et al. Curr Rheum Rep. 2009;11(5):378-385.
MAPKSignalingcascade
SYKSignaling cascade
NF-KBsignaling cascade
JAKsignaling cascade
Many cytokine receptors relay on associated tyrosine kinases, such as JAKs, to transmit signals from the extracellular environment to the nucleus1,2
Cytokine SignalingCytokine Signaling
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Monitoring the Safety of Methotrexate Therapy
• Laboratory monitoring: every 6-8 weeks– Complete blood counts– Serum transaminase levels– Serum albumin– Serum creatinine
• Folic acid supplementation should be:– At least 5 mg weekly
• Stop treatment in case of respiratory symptoms possibly related to MTX– Admit or consult with pulmonologist immediately in case of
serious disease
Pavy et al. Joint Bone Spine. 2006;73:388.
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Hochberg, et al. Semin Arthritis Rheum. 2005;34:819; Keystone et al. J Rheumatol Suppl. 2005;74:8; Schiff et al. Ann Rheum Dis. 2006;65:889; Scott and Kingsley. N Engl J Med. 2006;355:704.
Safety Considerations With Biologic Agents
• Serious infections– Patients with RA are at higher risk than the general population– Do not initiate in patients with active infections– Monitor closely, hold and consider discontinuing if a serious
infection develops
• Opportunistic infections (TB)– Includes histoplasmosis, listeriosis, pulmonary aspergillosis,
Pneumocystis carinii pneumonia– Patients should be screened for TB prior to use
• Reevaluation on a yearly basis?
• Hepatitis B screening
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Hochberg et al. Semin Arthritis Rheum. 2005;34:819; Keystone et al. J Rheumatol Suppl. 2005;74:8; Schiff et al. Ann Rheum Dis. 2006;65:889; Scott and Kingsley. N Engl J Med. 2006;355:704.
Safety Considerations With Biologic Agents (cont'd)
• Lymphoma– Patients with RA are at higher risk for lymphoma than the
general population – Risk for lymphoma may be increased in patients receiving TNF
antagonists
• Administration reactions
• Live vaccines are contraindicated– Pneumovax/influenza vaccination encouraged
• Demyelination– Rare; includes exacerbation of previously quiescent Multiple
Sclerosis, optic neuritis, Guillain-Barre syndrome
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Safety Considerations With Biologic Agents (cont'd)
• Hematologic abnormalities– Rare; includes cytopenia and pancytopenia
(including aplastic anemia)
• CHF
• Autoantibodies, SLE, and lupus-like syndrome– Rare; symptoms include cutaneous lesions, photosensitivity,
and pleural/pericardial serositis
• Combination of biologics not to be used– Increased risk of infection
Hochberg et al. Semin Arthritis Rheum. 2005;34:819; Keystone et al. J Rheumatol Suppl. 2005;74:8; Schiff et al. Ann Rheum Dis. 2006;65:889; Scott and Kingsley. N Engl J Med. 2006;355:704.
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RA Is an Independent Risk Factor for Cardiovascular Events*
18-49 50-64 65-74 75+Inci
denc
e Ra
te (p
er 1
000
pers
on-y
ears
)
Age Range (y)
Patients With RA (n=25,385)
Patients Without RA (n=252,976)
0
10
2030
40
50
60
70
Solomon DH et al. Ann Rheum Dis. 2006;65:1608-1612.
*Myocardial infarction, stroke.
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• A nationwide cohort of > 4 million patients was followed for ~10 years to examine risk of MI (heart attack)
• Risk of MI in RA patients was similar to the risk in those without RA who were 10 years older
Results from fully adjusted Poisson regression analysis (stratified by age in 10-year intervals).
Risk of MI in RA Patients Comparable to Risk of MI in Diabetics
100
80
60
40
20
0
<40 40-50 50-60 60-70 70-80 >80
Age group (years)
Inc
ide
nc
e r
ate
ra
tio
(IR
R)
General population
Rheumatoid arthritis
Lindharsen J et al. Ann Rheum Dis 2011;70:929–934.
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Mortality in Patients With RA: Impact of Treatment
Mo
rtal
ity
haz
ard
rat
io*
Prednisone MTX TNF Inhibitors
*Adjusted for severity, comorbidity, and demographic variables. Michaud and Wolfe. EULAR, 2005. Abstract OP0095.
N=19,580
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Conclusions
• RA is more than just a joint disease, but has important systemic implications
• Traditional drug therapy, despite its effectiveness, has limitations
• Improved understanding of pathogenesis has led to new biologic therapies with targeted mechanisms of action
• Safety issues are important with all therapies
• Current and future research is aimed at finding better ways to select and apply available options
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Working with your physicians
• Goal-directed therapy leads to the best outcomes – Know your goals
• Understand your medications – all medications have side effects, but so does untreated disease
• Beyond medications – a comprehensive approach to healthy living is important: diet, activity, cardiovascular risks
• Know your team – rheumatologist, primary care physician, physical therapist, you: all have an important role to play