Burden of Rheumatoid Burden of Rheumatoid ArthritisArthritis

Burden of Rheumatoid ArthritisBurden of Rheumatoid Arthritis

IndividualIndividual– Joint destructionJoint destruction– Collateral damageCollateral damage– PsychologicalPsychological– SocialSocial– FinancialFinancial

SocietySociety– WorkWork– Healthcare costsHealthcare costs– Social care costsSocial care costs

Burden of Rheumatoid ArthritisBurden of Rheumatoid Arthritis

Disabling condition affecting 0.5-1% of the Disabling condition affecting 0.5-1% of the worldwide populationworldwide population

Women more likely affected than menWomen more likely affected than men

Average age of onset = 45; prevalence Average age of onset = 45; prevalence increases with ageincreases with age

Medical costs are 2-3 times higher than Medical costs are 2-3 times higher than averageaverage

Lost productivity costs are 2-3 times higher Lost productivity costs are 2-3 times higher than medical coststhan medical costs

Case 1: CH 25 femaleCase 1: CH 25 femaleBackground Background

3-month history of 3-month history of generalised joint generalised joint stiffnessstiffness

1 month pain and 1 month pain and swelling in fingers and swelling in fingers and wristswrists

No recent history of No recent history of significant infectionssignificant infections

Case 1: CH 25 femaleCase 1: CH 25 femaleBackgroundBackground

Examination showsExamination shows– General examination normalGeneral examination normal– Swelling of MCPs and PIPsSwelling of MCPs and PIPs– Tender MCPs and PIPsTender MCPs and PIPs– Tender MTPsTender MTPs– Reduced range of movement of Reduced range of movement of

shouldersshoulders– DAS28 5.7DAS28 5.7

Case 1: CH 25 femaleCase 1: CH 25 femaleStandard investigations Standard investigations

InvestigationsInvestigations– Hb 10.7 g/dLHb 10.7 g/dL– Plts 425 x10Plts 425 x1099/L/L– ESR 42 mm/hrESR 42 mm/hr

– Biochemistry normalBiochemistry normal– CRP 37 mg/LCRP 37 mg/L

– ANA –veANA –ve– RF 50 IURF 50 IU

X-rays hands and feet X-rays hands and feet normalnormal

Case 1: CH 25 femaleCase 1: CH 25 femaleFurther investigationsFurther investigations USS handsUSS hands

– Synovitis in MCPs with increased Synovitis in MCPs with increased vascularity and suggestion of small vascularity and suggestion of small erosion in head of 4th MCerosion in head of 4th MC

Anti-CCPAnti-CCP– Strongly positiveStrongly positive

Age Distribution of Rheumatoid Age Distribution of Rheumatoid ArthritisArthritis

65 to 74 yrs27%

75 to 84 yrs15%

> 84 yrs2%

10 to 19 yrs2%

60 to 64 yrs11%

40 to 59 yrs35%

20 to 39 yrs8%

Burden of Rheumatoid ArthritisBurden of Rheumatoid Arthritis

Inflammatory disorder primarily of the Inflammatory disorder primarily of the jointsjoints

Progressive disease with flare-upsProgressive disease with flare-ups

70% have joint damage within 2 years70% have joint damage within 2 years

25% have severe functional problems 25% have severe functional problems after 10-15 years of diseaseafter 10-15 years of disease

16% likely to need hip or knee 16% likely to need hip or knee replacementreplacement

The Burden of RA:The Burden of RA:Collateral DamageCollateral Damage

The Burden of RA: Collateral The Burden of RA: Collateral DamageDamage

Kirwan JR. J Rheumatol. 2001;28:881-886; Scott DL. Rheumatol. 2000;39:24-29.

InflammationDisabilityRadiographsCollateral damage

Severi

ty

0

Duration of Disease (Years)

5 10

15

20

25

30

Early Intermediate Late

© ACR

CH 63 femaleCH 63 female

RA 15 years agoRA 15 years ago

RF strongly positiveRF strongly positive

DAS28 2.8–3.5DAS28 2.8–3.5

CRP 5–10CRP 5–10

Treated Treated – MTX 20mg/wkMTX 20mg/wk– SSZ 1gm bdSSZ 1gm bd– IM depomedrone IM depomedrone

PRNPRN

Erosions MCPsErosions MCPs

Knee pain with loss Knee pain with loss of joint spaceof joint space

Other medical Other medical problemsproblems– MI inferior 6 years MI inferior 6 years

ago ago – NIDDMNIDDM– OsteoporosisOsteoporosis

CH 63 femaleCH 63 female

Collateral Damage in RA: Collateral Damage in RA: Cardiovascular diseaseCardiovascular disease

Patients with RA are at an increased risk of Patients with RA are at an increased risk of cardiovascular disease (CVD)cardiovascular disease (CVD)

Mortality due to CVD is increased by 50-Mortality due to CVD is increased by 50-100% in patients with RA 100% in patients with RA • There is also an increase in CVD morbidity in RAThere is also an increase in CVD morbidity in RA

Independent of traditional risk factorsIndependent of traditional risk factors

del Rincon ID et al. Arthritis Rheum 2001; 44; 2737–45.

Burden of RA: IHD in RABurden of RA: IHD in RA

Predictor IRR for MI 95% CI p-value

RA 2.23 (2.07, 2.41) <0.001

RA (*adjusted) 2.04 (1.82, 2.30) <0.001

GPRD 34,963 RA cases & 103,092 controlsGPRD 34,963 RA cases & 103,092 controls

No difference in DM, HTN, anti-hypertensives or statinsNo difference in DM, HTN, anti-hypertensives or statins

*adjusted for Age, Sex, HTN, DM, Smoking, BMI, Anti-HTN drugs, Lipid-lowering drugs ever before MI & DMARDs/Pred. at time of MI

Edwards et al ACR OP 687/688 2008

Quality of LifeQuality of Life

Health-related quality of life

Rapp S et al., J Am Ac Dermatol 1999;41:401-407.

0 20 40 60 80 100 120

Healthy individuals

Psoriasis

Arthritis

Cancer

Arterial hypertonia

Myocard. infarction

Cong. heart failure

Depression Physical

Mental

Physical and Mental Component Summary Score

Rheumatic Disease is a Leading Rheumatic Disease is a Leading Cause of DisabilityCause of Disability

2.8

3.3

3.4

3.7

4.2

4.4

4.7

7.8

16.5

17.5

0 5 10 15 20

Stroke

Blindness

Diabetes

Mental condition

Limb weakness

Deafness

Respiratory condition

Heart condition

Back or spine condition

Arthrits or rheuamtic disease

Percent of all disabilities

Persons aged 15 years and olderCDC. Morbidity and Mortality Weekly Report. 2001. 50(7): 120-125.

Evidence base for psychological impact of inflammatory Evidence base for psychological impact of inflammatory diseases is well-establisheddiseases is well-established

Psoriasis: 5.5% active suicidal ideation, 9.7% wish to be Psoriasis: 5.5% active suicidal ideation, 9.7% wish to be deaddead99; Suicidal ideation: outpatients 2.5%; inpatients ; Suicidal ideation: outpatients 2.5%; inpatients 7.2%7.2%1010

Rheumatoid arthritis: 11% outpatients reported suicidal Rheumatoid arthritis: 11% outpatients reported suicidal ideationideation1111

The psychosocial impact of The psychosocial impact of inflammatory diseaseinflammatory disease

Rheumatoid ArthritisRheumatoid Arthritis• DisabilityDisability55

• DepressionDepression6,76,7

• AnxietyAnxiety88

Psoriasis Psoriasis • DisabilityDisability11

• WorryWorry22 • AnxietyAnxiety33

• DepressionDepression44

1. Finlay & Coles. Br J Dermatol 1995; 132: 236-244; 2. Fortune et al. Br J Heal Psychol 2000; 5: 71-82; 3. Richards et al. J Psychosom Res 2001; 50: 11-15; 4. Esposito et al. Dermatol 2007; 212:123-127; 5. Hill et al. Clin Rheumatol 2007; 26:1049 – 1054; 6. Pincus et al. Br J Rheumatol 1996; 35:879-833; 7. Escalante et al. Arthritis Care Res 2000; 13: 156–167; 8. Katz & Yelin. Arthritis Care Res 1994; 7: 69-77. 9. Gupta et al. Int J Dermatol 1993; 32:188-190; 3.Gupta et al. Br J Dermatol 1998; 139: 846-850 4. Treharne et al. BMJ 2000; 321: 1290

Quality of Life of Patients with RA Quality of Life of Patients with RA vs. Patients with Other Chronic vs. Patients with Other Chronic ConditionsConditions

0

10

20

30

40

50

60

70

80

90

Congestive Heart Failure Acute Myocardial Infarction

Clinical Depression RA

Direct & Indirect Cost of RADirect & Indirect Cost of RA

RA is Associated with RA is Associated with Significant Direct and Indirect Significant Direct and Indirect CostsCosts Compare economic burden to society Compare economic burden to society

incurred by patients with RA, OA or HBPincurred by patients with RA, OA or HBP

Information collected on demographics, Information collected on demographics, health status, comorbidities, and health status, comorbidities, and resource utilizationresource utilization– RA = 253 patientsRA = 253 patients– OA and/or HBP = 473 patientsOA and/or HBP = 473 patients

Direct and indirect costs highest for Direct and indirect costs highest for patients with RApatients with RA

Maetzel A, et al. Ann Rheum Dis. 2004; 63: 395-401.

The Cost of RA by Functional Level

Direct costs Indirect costs£1 = SEK 15; €1 = SEK 9.3, £0.6

0

50

100

150

200

250

300

<0.6 0.6 <1.1

1.1 <1.6

1.6 <2.1

2.1 <2.6

>2.60

2

4

6

8

10

12

14

16

<0.6 0.6 <1.1

1.1 <1.6

1.6 <2.1

2.1 <2.6

>2.6

Sw

edis

h K

rono

r (S

EK

100

0)

UK

Ste

rling

(£

1000

)

Sweden UK

Kobelt G et al. Arthritis Rheum. 2002;46:2310-9.

Pathogenesis of Pathogenesis of Rheumatoid Arthritis (RA)Rheumatoid Arthritis (RA)

The Inflammatory Cascade in The Inflammatory Cascade in RARA Activation of T cells Activation of T cells

triggers a series of triggers a series of intercellular reactionsintercellular reactions11

Lymphocytes, Lymphocytes, monocytes/ monocytes/ macrophages, and macrophages, and synovial fibroblasts are synovial fibroblasts are stimulated to release stimulated to release proinflammatory proinflammatory cytokinescytokines22

Cytokines induce synovial Cytokines induce synovial proliferation and release proliferation and release of destructive enzymesof destructive enzymes1-31-3

B Cell

T Cell

Macrophage

Pannus

Cartilage

TNF

IL-1

Mechanisms of Structural Mechanisms of Structural Damage in Rheumatoid Damage in Rheumatoid ArthritisArthritis11

CD4+T lymphocyte

Macrophage

Endothelial cell

Osteoclasts

Bonedestruction

Jointerosion

Synoviocytes

Cartilagedestruction

Joint-spacenarrowing

Chondrocytes

Adhesion moleculeexpression

TNFIL-1

TNFIL-1

Adapted from Arend WP.  J Rheumatol Suppl. 2002;65:16-21. Permission to reproduce granted by Journal of Rheumatology and Dr WP Arend.

Cytokine Disequilibrium in the Cytokine Disequilibrium in the Disease Process of RADisease Process of RA1,21,2

Proinflammatory

TNF

IL-8

IL-1

IFN-

IL-2

LT

IL-6

Anti-inflammatory

IL-4

IL-10 sIL-1R

IL-11IL-1Ra

TGF-

sTNFR

The Role of TNFThe Role of TNF

TNF – A Logical TargetTNF – A Logical Target

Helps drive events in the Helps drive events in the inflammatory cascadeinflammatory cascade1-31-3

Triggers production of other Triggers production of other cytokines, including IL-1cytokines, including IL-11,21,2

Proinflammatory

IL-6, IL-8, GM-CSFIL-1

TNF

Anti-inflammatory

IL-10, sTNFR, IL-1Ra,

Three Destructive Effects of Three Destructive Effects of TNFTNF1-51-5

Inflammation

Activates monocytes/macrophages

Bone resorption and erosions

Activates osteoclasts, suppresses osteoblasts

Cartilage breakdown

Activates chondrocytes,

releasing collagenases

SummarySummary

– RA is the most common inflammatory RA is the most common inflammatory arthritisarthritis

causes severe joint destructioncauses severe joint destruction is a systemic disease with systemic damageis a systemic disease with systemic damage leads to disabilityleads to disability Is associated with significant costsIs associated with significant costs Is an immune mediated disease driven by Is an immune mediated disease driven by

inflammatory cytokinesinflammatory cytokines

Managing RA – Therapeutic Managing RA – Therapeutic GoalsGoals Control symptomsControl symptoms

Minimize loss of functionMinimize loss of function

Reduce progression of diseaseReduce progression of disease

Burden of Rheumatoid ArthritisBurden of Rheumatoid Arthritis

Almost all patients have daily pain Almost all patients have daily pain and functional lossand functional loss

Over time disease leads to structural Over time disease leads to structural damage and premature mortalitydamage and premature mortality

RA patients have lower QOL than RA patients have lower QOL than patients with other chronic diseasespatients with other chronic diseases

Collateral damage - CV, bone etcCollateral damage - CV, bone etc

Additional SlidesAdditional Slides

TNF – A Logical Target

• TNF is involved in the disease process of Rheumatoid Arthritis (RA) at multiple levels3-7,9,10:

• Activates immune cells, promoting an inflammatory response

• Binds to chondrocytes and osteoclasts, triggering multiple destructive effects

• Induces expression of adhesion molecules, promoting the migration of T cells into the synovium

• Stimulates production of other proinflammatory cytokines

• With these effects, TNF is a logical target for therapeutic intervention

Two Approaches to TNF Inhibition1-5

Fc regionof human

IgG1

Extracellular domain of human p75 TNF receptor

(binding site for TNF)

Etanercept (human soluble receptor)

Soluble Receptor

Adalimumab (human MAb)

Infliximab (chimeric MAb)Anti-TNF Monoclonal Antibodies (MAbs)

Human variable region (binding site for TNF)

Human (IgG1)

Murine region(binding site for TNF)

Human (IgG1)

Demand for health care and medicines is a derived demand for improved health

Two sources of value– Health as an input to production– Health as an input to consumption

Medicine offers opportunities for investing in improved health

Medicine and Health

0,0

0,1

0,2

0,3

0,4

0,5

0,6

0,7

0,8

0,9

1,0

Util

ities

by

dise

ase

stat

e (E

Q-5

D)

< 0.6 0.6<1.1 1.1<1.6 1.6<2.1 2.1<2.6 >=2.6

Disease states by HAQ

Sweden

UK

Utility and Health Status

Kobelt G et al. Arthritis Rheum. 2002;46:2310-9.

How is Value Measured?

Cost consequence analysis– Costs and outcomes presented

Cost minimisation analysis– Costs compared, outcomes equivalent

Cost effectiveness analysis– Costs and clinical outcome presented

Cost utility analysis– Costs in monetary units, outcomes in Quality Adjusted

Life Years

Cost benefit analysis– Costs and outcomes presented in monetary terms

80%

Workforce Participation at Different Levels of RA Severity

0%

20%

40%

60%

0-0.5 0.5-1.0 1.0-1.5 1.5-2.0 2.0-3.0

52 52 54 52 57

HAQ Groups

% of Patients below 66 working (Sweden 2002)

Mean age

Kobelt G et al, Rheumatology 2005;44:1169-75.

Treatment Costs for RA Annual cost per patient treated

Old drugs

Methotrexate– Introduced 1950s– €400

High value and affordability

Do not work for all patients

New drugs

Anti-TNFs– €15-20 000

High value

Affordability a problem

Optimal treatment strategies must be designed

The demand for health is determined by income and price

Third party payment will not eliminate the scarcity of resources for medicines and improvements in health

Why cannot third party payers price discriminate?– Based on the assumption that markets

can be kept separated

Value and Ability to Pay

Summary Cost-.effectiveness studies have been widely used for decisions

on resource allocation in RA

Methodology for economic assessment in RA well developed– QALY as outcome measure universally accepted– Modeling progression and changes in costs and utilities with treatment over long

term

Models can only represent the underlying data– Clinical trial population, costs, utilities

Results can in addition differ due to– Perspective chosen, time horizon, country

WIth the exception of NICE models, cost-effectiveness ratios range between €20-50,000 for the type of patient included in the clinical studies modeled

Registry data will to some extent allow verifying modeling results

Outcome and Cost-Effectiveness