with additional gratitude

to our scientific partners

AOSSM, FNIH, NIAMS

and OARSI

and to

Gordon & Carole Segal

OPENING SESSION

OSTEOARTHRITIS:

CLASSIFICATION, RISK FACTORS, THERAPEUTIC & CLINICAL TRIAL

IMPLICATIONS

JOHN A. HARDIN, MD

A Cause for Urgency- The personal impact -

• 50 million Americans have arthritis.• 9.5 million Americans are disabled by

arthritis.• 8 million Americans are disabled by

back pain.

• In contrast, 3 million Americans are disabled by heart disease.

A Cause for Urgency- The Cost -

• Arthritis accounts for almost 10% of our nations total health care costs.

• Back pain is a leading cause of lost productivity in the workplace.

CLINICAL SUBSETS OF OA/UNIQUE PATHWAYS TO

JOINT FAILURE

JOEL BLOCK, MDCHAIR

DAVID T. FELSON, MD, MPH

An Overview of the Epidemiology of Osteoarthritis

David T. Felson MD MPHBoston University School of Medicine

Definition of Osteoarthritis• A painful disorder in which local areas in a joint are

damaged• All structures within the joint can be affected:

– Hyaline Cartilage loss (the defining feature) and fibrocartilage degeneration/loss

– Bone remodelling and sclerosis– Chondro-osteophytes– Capsular thickening and distension– Synovial inflammation– Muscle atrophy and weakness

Outline of Talk

• The prevalence and impact of OA now and in the future

• What are the risk factors for OA?• Could OA be several different diseases and

which ones?

The Prevalence of Osteoarthritis (OA)

• The most common type of arthritis. – Of those > 65 years,

• 11% have painful knee OA• 5 % have painful hip OA

– Of those age 30 and over, 6% have knee OA; 2% have hip OA;

– Risk rises with age: by age 85, 45% of persons will get painful knee OA (higher if obese)

Prevalence of Knee Pain and Osteoarthritis in Persons Age 55 and Over

0 1000 2000 3000 4000 5000 6000 7000 8000 9000 10000

People aged 55+years

4 Weeks of kneepain in past year

Knee pain and somedisability

Knee pain andsevere disability

Population of adults aged 55+ years

160

1250

2500

10000

Shading represents the proportion in each category with radiographic evidence of knee osteoarthritis.

Is Symptomatic OA Much More Common than We Estimated?*

*From Cibere et al, AC+R,2010

Impact of Osteoarthritis

• Cuts 1.9 years on average from the remaining number of healthy years. (Losina et al, 2011)

• In the elderly, accounts for more lower extremity disability than any other disease (Guccione et al, 1994)

• Accounts for most total knee and hip replacements

• Shortens life (Nuesch et al, 2011)

Painful Osteoarthritis: Future Shock in U.S.

27 million currently affected

40 million affected in 2020

Aging of the population

Increasing obesity

Increased sports related injuries

Systemic

Factors

Affecting

Joint

Vulnerability

Older Age

Female Gender

Caucasian Race (hip)

Genetic Susceptibility

Intrinsic Joint Vulnerabilities (Local Environment):

Previous Damage (e.g. torn meniscus; ACL)

Bridging Muscle Weakness

Cartilage unable to repair

Periph. Nervous System impairment

Malalignment across joint

Misshapen Joint (hips)

Joint Susceptibleto O.A.

Loading

Factors

Acting on

Joints :

Obesity

Injurious Physical Activities

Osteoarthritis or Its Progression

OBESITY AND KNEE OSTEOARTHRITIS IN CAUCASIAN FEMALES*

OBESITY AND KNEE OSTEOARTHRITIS IN CAUCASIAN FEMALES*

Age Normal Overweight Obese25-34 0 .3% 2.2%35-44 0 .3% 11.1%45-54 .5% 1.9% 13.2%55-64 2.6% 5.2% 17.5%65-74 5.8% 17.7% 49.0%

Percent with Radiographic Knee Osteoarthritis (> Grade 2)

*from Anderson and National Center for Health Statistics

Is Osteoarthritis More than One Disease? (does it consist of >1

phenotype?)

Phenotype• Wikipedia: A phenotype is an observable characteristic or trait of an

organism such as its morphology, development, biochemical or physiological properties, or behavior.

• Observable characteristic: observable by naked eye/images/blood tests

• Genotype expression can create phenotype variation

• Phenotype = subtype

• We shall define a subtype ONLY when it is important as follows:– Affects treatment (e.g. estrogen receptor +/- breast cancer)– Changes prevention approach (e.g. BRCA)– Alters conceptual approach/biology of disease (e.g. H Pylori)

Could Phenotype be Relevant in OA?

• OA: final common pathway of joint destruction for multiple etiologies (trauma, developmental, primary cartilage disorder, crystal)

• OA: collection of different disorders producing common phenotype

IDENTIFYING PHENOTYPES (SUBTYPES) MAY BE CRITICAL TO DEVELOPMENT OF EFFECTIVE TREATMENT/PREVENTION

What Factors Define Phenotypes?

– Genetics (e.g. BRCA; EGFR Mutation)

– Risk/Etiologic Factors: (e.g. developmental abnormalities in hip OAearly surgery)

– Severity (e.g. TNM classification for a variety of cancers)

Are Phenotypes Likely to be Important in OA?

– If treatment only works in phenotype, we will miss effect in all disease patients (e.g. treatment targeted to bone marrow lesions)

– If treatment does not work in subtype and subtype is common, may miss effect of treatment on disease (e.g. malalignment of knee creates too much stress for chondroprotective agent to work.

Percent of Knee OA Due to Hypothesized Causes of Knee OA

Questions Addressed

1 Based on evidence, what are the likely subtypes of OA?

2. How will we determine/confirm subtypes?

Which Phenotypes are supported by Evidence in OA?

• Generalized vs. Joint Specific (Hand/Knee/Hip) OA

• Secondary (Cause identified; acts alone) vs. Primary OA (idiopathic; network of risk factors)

• Painful vs. nonpainful joints (50% of persons with X-ray OA have little, if any, pain in affected joint)

-Dysfunctional vs. functional pain

• Malaligned vs. nonmalaligned joints

GDF-5 snp and Hip OA: Meta-analysis

Evangelou et al, 2009

GDF-5 snp and Knee OA: Meta-analysis

GDF-5 snp and Hand OA: Meta-analysis

Grade 1

From Rheumatol 2009

Secondary vs. Primary OA Example: Meniscal Tear and Knee OA

Percentage of Knees with Degenerative Changes after Meniscal Removal

Compared to Opposite (Unoperated) Knee

Years of Follow-up <10 10-19 20-29 30-40

Meniscectomy 21% 23% 53% 67%

Contralateral Knee 4% 4% 13% 0%

Which Phenotypes are supported by Evidence in OA

• Generalized vs. Joint Specific (Hand/Knee/Hip) OA

• Secondary (Cause identified; acts alone) vs. Primary OA (idiopathic; acts with network of other factors)

• Painful vs. nonpainful joints (50% of persons with X-ray OA have little, if any, pain in affected joint)

-Dysfunctional vs. functional pain

• Malaligned vs. nonmalaligned joints

Evidence of Inadequate Diffuse Noxious Inhibitory Control in Hip OA (generalized pain)

Kosek and Ordeberg, OA&Cartilage, 2000

One Probable OA subtype: Malaligned Joints

• Malaligned vs. nonmalaligned: potent effect on progression

-high focal stress with malalignment that may transcend ability of joint cartilage/bone to withstand it.

-bone marrow lesions, traumatic lesions in bone, associated with malalignment malalignment damages bone

• In malaligned knees, effects of other risk factor eliminated

• Implications Treatment targeted to cartilage protection will not work in malaligned knees

BMI and Its Effect on Incident vs. Progressive OA

From Niu et al, 2008

Which Phenotypes of OA exist based on Current Evidence?

• Generalized vs. Localized OA• Secondary vs. Primary OA? (secondary more

common than previously believed)• Painful vs. Nonpainful OA; subtype with

dysfunctional pain• Malaligned vs. nonmalaligned Joints with OA:

response to treatment may differ

Methods for Finding Distinct OA Phenotypes

– Factor or Cluster analysis: statistical approach

– Genome Wide Association Study (GWAS) : investigate phenotype specific SNP’s (must have good data on phenotypes in the data sets)

– Epidemiologic: test if other major risk factors affect

risk the same way in those with and without the phenotype (e.g.malalignment)

– Make guesses based on biology and confirm them in 2 or more studies (e.g. from lung cancer)

How to Identify or Confirm Phenotypes?

• Large studies best for identifying subtypes even initially

• Subtype must define response to treatment or prevention strategy or must provide evidence that there are important biologic differences among types of disease

• Confirmation in independent studies critical (see work by Ioannidis in GWAS studies)

Conclusions

• OA is a remarkably common, painful and disabling disorder

• It will become more common• Risk factors include: aging, obesity, genetics,

joint injury and as yet other unknown factors

Conclusions about Phenotypes in OA

• In OA identifying different phenotypes may be critical to treatment/prevention/disease biology

• Phenotypes of OA include: – Generalized vs. Joint Specific OA– Painful vs. Nonpainful (and in those with pain,

functional vs. dysfunctional pain likely subtypes)– Secondary vs. Primary OA (more secondary)– Malaligned vs. neutrally aligned knee OA (probable)

• Identifying new phenotypes will be challenging and requires multiple replicative studies

Appreciations

• Funding: NIAMS, NIA and the Arthritis Foundation

• Specific thanks for help in thinking about phenotypes go to: Tuhina Neogi, Yuqing Zhang, Jingbo Niu and the Clin Epi Group at B.U.

Effect of Obesity on Progression by Limb Alignment Status

Felson et al, 2004

Prevalence of Knee Pain and Osteoarthritis in Persons Age 55 and Over

Population of adults aged 55+ years

160*

1250

2500

10000

* The proportion with radiographic evidence in this category is not known, though seems likely to be high.Dark shading represents the proportion in each category with radiographic evidence of knee osteoarthritis.

Persons withX-ray OA

Other Possible Phenotypes in OA

Within Joint Genetic Phenotypes

Painful vs. nonpainful (50% of persons with X-ray OA have little, if any, pain in affected joint)

-Generalized pain vs. functional pain

Malaligned vs. nonmalaligned (is this real or a function of difficulties studying progression)

Percent of Progressive Knee OA Among Knee OA cases

Meniscus and OA: Up to 40% of persons age 50/60/older have meniscal tearsThose with tears have marked increased risk of OA (Englund, A+R, 2009)Up to half of knee OA may be due, in part, to tearsCould other more subtle injuries account for the rest?

Englund et al, NEJM, 2008

Malalignment & OA Progression

• 240 subjects with knee OA followed 18 months• Varus (bowlegged) 3.5 fold increased

risk (p<.001) for medial progression• Valgus (knockneed) 3.8 fold increased

risk (p<.001) for lateral progression• Severe varus or valgus knees with worsening pain

and disability

Sharma, L et al,, JAMA, 2001.

STEFAN LOHMANDER, MD, PhD

NIZAR MAHOMED, MD

RICHARD F. LOESER, JR., MD

JOHN LOUGHLIN, PhD

THE JOINT AS AN ORGAN:Identifying Targets for Intervention

MARY GOLDRING, PhD,CHAIR

ROBIN A. POOLE, PhD, DSc

STEVEN R. GOLDRING, MD

CARLA R. SCANZELLO, MD, PhD

LAWRENCE BONASSAR, PhD

VANIA APKARIAN, PhD

OA RISK FACTORS:Can They Be Addressed

Therapeutically?

JOHN SANDY, PhDCHAIR

THOMAS ANDRIACCHI, PhD

JOSEPH BUCKWALTER, MD

RICHARD F. LOESER, JR., MD

MARTIN K. LOTZ, MD

EVALUATION OF OA DIAGNOSIS AND PROGRESSION

MARC HOCHBERG, MD, MPHCHAIR

VIRGINIA KRAUS, MD, PhD

HOLLIS POTTER, MD

GARRY GOLD, MD

TOM ANDRIACCHI, PhD

WHAT HAVE WE LEARNED ABOUT OA

FROM ANIMAL MODELS?

Kenneth D. Brandt, MDUniversity of Kansas Medical Center

Although the most obvious pathologic changes in an OA joint are usually seen in the articular cartilage, ALL of the tissues of the joint are involved, including the subchondral bone, synovium, muscles, nerves and ligaments.

Previous definitions of OA have been far too chondrocentric. The etiopathogenesis of OA is very

differentfrom the pathogenesis of articular cartilage breakdown in OA.

ETIOPATHOGENESIS OF OA

Advanced OA of the Knee

Osteoarthritis (OA) is NOT

a degenerative joint disease (“DJD”).

The real problem isn’t OA;

it’s painful OA.

Neurogenic Acceleration of OA

? Post-Rehabilitation Arthritis

ADVANCING THE CARE OF PATIENTS WITH OA

THE PATIENT PERSPECTIVE

KENT KWOH, MDCHAIR

Robin Katzanek, PT, MA, PhD

Osteoarthritis Advisory Group

Osteoarthritis Advisory Group

We represent a community of people who share a personal and common interest in eliminating arthritis as the leading source of disability in this country

Osteoarthritis Advisory Group

We voice the needs of the OA community to Arthritis Foundation leadership regarding the prevention, control and cure of osteoarthritis

We put a face on OA as a life-altering disease

One of 27 million with OA

• Diagnosed at age 30 years

• Years of running and other athletic pursuits

• Multiple meniscectomies

Physical Therapist

• 42-year-old groundskeeper• 46-year-old mother of three• 53-year-old laborer

Concerns of People with OA

• Pain• Medication• Surgery• Lifestyle• Disease Progression

What Do We Want?• Limit medications & their

side effects• Work

What Do We Want?

• Disease control• Enjoy activities• Live life to its

fullest

MARCY O’KOON

PATIENCE WHITE, MD

GILLIAN HAWKER, MD, MSc

JOANNE JORDAN, MD, MPH

CLINICAL TRIAL DESIGN

THOMAS SCHNITZER, MD, PhDCHAIR

MARC HOCHBERG, MD, PhD

ELENA LOSINA, PhD

GAYLE LESTER, PhD

LINDA SANDELL, PhD

• JEFFREY KRAINES, MD

• MARIE-PIERE HELLIO LE GRAVERAND-GASTINEAU, MD, DSc, PhD

• PETER MITCHELL, PhD

• GLORIA MATTHEWS, DVM

• ROY BLACK, PhD

• BROOKS STORY

A PLAN FOR ACTION

NEXT STEPS

JOHN ESDAILECHAIR

AF RESOURCES/PRIORITIES

JOHN A HARDIN, MD

PUBLIC/PRIVATE PARTNERSHIPS

ERIC NELSON

REPORT FROM THE AOSSM

CONSTANCE CHU

BREAKOUT SESSIONS:PURPOSE & GOALS

ROBIN A. POOLE, PhD, DSc

GROUP DISCUSSION

FUTURE ACTIVITIES FOR ADVANCING THE GOALS

TREATMENT OF OA