Living with Rheumatoid Arthritis:

Understanding Options, Understanding Goals

Eric Ruderman, M.D.Professor of Medicine, Rheumatology

Northwestern University Feinberg School of Medicine

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.

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.

Images courtesy of J. Cush, 2005.

The Clinical Spectrum of RA

Active with some deformity

Early PIP swelling Late-stage deformities

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

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

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

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

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

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.

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

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.

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

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

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

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.

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

ActivatedActivatedMacrophageMacrophage

TargetTargetCellCell

SignalSignal

sTNFR

sTNFR

TNFTNF

TACETACE

TACETACE

TNF and TNF Receptors

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

ActivatedActivatedmacrophagemacrophage

TargetTargetcellcell

TNFTNF

p55p55

p75p75

anti-TNF Abanti-TNF Ab

TNF Inhibition: Monoclonal Antibodies

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.

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

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

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.

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

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

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.

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.

• 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.

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

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

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