Osteoarthritis: Etiology, Pathogenesis and Treatment Considerations Lee S. Simon, MD Associate Clinical Professor of Medicine Beth Israel Deaconess Medical.

Osteoarthritis: Etiology, Pathogenesis and Treatment

Considerations

Lee S. Simon, MD

Associate Clinical Professor of Medicine

Beth Israel Deaconess Medical Center

Harvard Medical School

Osteoarthritis• Typically affects people over the age of 50• A biologic process which effects cartilage with

subsequent inflammatory component• Characteristically the major component of the

clinical presentation is pain and decreased function– >75% of people over the age of 75 have x-ray evidence

of disease– > 75% of people over the age of 85 are symptomatic

• Probably affects 16-20,000,000 Americans

Prevalence of Rheumatic Disorders

1050

200

500

1090

3500

5500

7000

10000

2000*

0 2000 4000 6000 8000 10000 12000

Other Arthritis

Ankylosing Spondylitis

Rheumatoid Arthritis

Gout/Pseudogout

Fibromyalgia

Osteoarthritis

Bursitis/Tendinitis

Osteoporosis

Neck and Back Pain

Prevalence (per 100,000)*8000 if subthreshold included.Adapted from Marder WD. Arthritis Rheum. 1991;34:1209–1217.

The Joint as an OrganThe Joint as an Organ

• Cartilage (hyaline, fibro-cartilage)– Hyaline: predominantly type II collagen– Fibrocartilage: predominantly type I collagen

• aneural • avascular • alymphatic• limited capacity for repair after injury

• Menisci (medial, lateral)• Tendons, ligaments,capsule • Bone,periosteum• Synovial fluid/membrane• Muscles

Structure of CartilageStructure of Cartilage

Risk Factors

• Genetics– Abnormal components of the joint as an organ– Abnormal range of motion– Congenital anomolies

• Trauma• Overuse syndromes• Post-infectious• Obesity

Etiopathogenesis

• Normal cartilage and supporting structures subjected to abnormally increased loads– Obesity– Overuse syndromes

• Abnormal cartilage and supporting structures subjected to either minimal loads or abnormally large loads– Inherited defects of structural components (e.g. type II

collagen, cartilage lysis syndrome, hypermobile syndromes)– Ochronosis

OA Biology• Slowly progressive disease• Primarily initially affects cartilage

– Early cellular response: increased synthesis of proteoglycans and collagen followed by increased hydration

– Then later inability to keep up with repair process and failure to replace proteoglycans and collagen

– Consequent loss of cartilage, fissuring of cartilage, subchondral bone sclerosis and finally eburnation with “bone on bone”

• Subsequent inflammatory response to cartilage effects– Clear synovial hypertrophy with consequent stimulus of

inflammatory cytokines (IL-1 and TNF alpha have been shown to be elevated in the joint fluid)

– But these effects are more local: little increase in CRP, few signs and symptoms of systemic inflammatory disease

Conceptual Model of OAConceptual Model of OABiochemical changes/ cells and tissue

Structural changes

Pain and other signs and symptoms

Functional limitation

Reduced quality of life

Surgical replacement

DIPs

PIPs CMCs

OA: Pattern of Joint Involvement

Base of big toe

Neck

Lower Back

Hips

Knees

Diagnosis of OA

• Symptoms– Pain– Decreased function

• Due to boney change • Due to soft-tissue change or swelling• Due to alteration of the normal structures

– Crepitance or “crunching within the joint”

Diagnosis of OA

• Signs– On physical exam

• Asymmetry of findings usually of large joints• Heberdens/Bouchard’s nodes (may be

symmetrical)– Classic hand involvement: DIP/PIP nodular disease

• Some boney swelling• Some swelling and pain out of proportion to

inflammatory findings

Typical OA Hand: Know It When You See It

• Hard boney enlargements

• Heberden’s nodes at the DIP joints

• Bouchard’s nodes at the PIP joints

• Often have “squared” first CMC joint due to osteophytes at that joint

Diagnosis of OA

• By imaging– X-ray

• Presence of osteophytes (biologic evidence of an attempt to repair?)

• Progressive joint space narrowing which is a surrogate measure of cartilage thinning

– Now known not to be linear and some patients are rapid progressors while others are slow progressors or somewhere in between; how to predict which patient falls into which category

• Increased sclerotic change in subchondral bone– When significantly progressive might reflect eburnation

Radiographic Features of the Knee in OA

• Joint space narrowing

• Marginal osteophytes

• Subchondral cysts• Boney sclerosis• Malalignment

Joint space narrowing

Diagnosis of OA

• Imaging– MRI

• Newer technique• Able to provide a 3 D image of the joint as an

organ– Can approximate the volume of cartilage– May be able to identify early change in cartilage

metabolism– Can approximate early bone change (bone

“edema”?)

Diagnosis of OA

• Biochemical markers– Sources of such markers

• Joint tissue/fluid– Synthetic products of the components of the joint– Products that reflect metabolism of the components of the

joint

• Blood– Circulating in serum: products of cartilage turnover

• Urine– Products of cartilage metabolism which are cleared by the

liver (or elsewhere) from the serum and then possibly further processed and then excreted in the urine

Diagnosis of OA

• Biochemical markers not yet adequate for diagnosis, identifying patients at risk, or measuring outcomes BUT:

• Biochemical markers may in the future with further refinement– be useful in exploratory studies – help identify “at risk” or “resistant” patients– help compare therapies– help patients and doctors to select and monitor therapies– help assess efficacy (? surrogate endpoint)

Definitions of Biomarkers and Surrogate Markers

Biomarker (biological marker) or imaging marker is a characteristic that is measured and evaluated as an indicator of normal biologic processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention.

Definitions

• Clinical endpoint- A characteristic or variable that measures how a patient feels, functions or survives.– VAS pain, WOMAC, HAQ, patient global

assessment

• Surrogate endpoint- A marker intended to substitute for a clinical endpoint.

A surrogate endpoint of a clinical trial is a laboratory measurement or a physical sign used as a substitute for a clinically meaningful endpoint that measures directly how a patient feels, functions, or survives. Changes induced by a therapy on a surrogate endpoint are expected to reflect changes in a clinically meaningful endpoint.

Temple - 1995

Questions Asked

• What valid modifiable risk factors/surrogate endpoints are there for predicting the risk of developing osteoarthritis in humans?– Obesity

• Clear opportunity to enrich a study outcome with more chance of having progressive disease especially if the patient has evidence of early OA (jsn, osteophytes)

• Low percentage of patients with progressive disease without evidence of incipient disease

Questions Asked

• What valid modifiable risk factors/surrogate endpoints are there for predicting the risk of developing osteoarthritis in humans?– Risk factors

• Obesity • Patients with repetitive use syndromes

– Surrogate endpoints• Joint space narrowing is evidence of progressive OA but may

or may not be associated with the important clinical component of symptoms

• Other observed x-ray changes are useful for diagnosis but are not important by themselves without clinical symptoms of disease

• There are no valid surrogate biochemical markers at this time

Questions Asked

• Are joint degeneration and cartilage deterioration:– Signs or symptoms of OA?

• Yes, in the absence of another explanation such as ongoing systemic inflammatory disease these are evidence in the context of symptoms of OA

– Modifiable risk factors/surrogate endpoints for osteoarthritis? • Not generally, the presence of the above findings are part and

parcel to OA; while JSN may be an important way to demonstrate that a structure modifying drug may be active. However, if there is improvement in structure it would be expected at sometime that there would be a linked improvement in symptoms at some time (perhaps even in the future)

– Patients present with pain or other symptoms: joint change and cartilage degeneration in some patients may be associated with pain and loss of function: but not all patients will have symptoms in the context of these changes

• Once a patient has pain, he will have evidence of change, but not all patients with changes will have symptoms

• A spectrum of disease, mild disease is still disease and associated with changed joint tissue whether or not measurable by presently available techniques

Therapy

• Presently is designed to improve modifiable risk factors– Reach ideal body weight in those that are obese

• Decrease body weight a significant decrease in symptoms– Alter life style behaviors such as those associated with overuse

syndromes• Mostly palliative to decrease symptoms of pain leading hopefully

to an improved health related quality of life– Analgesics/anti-inflammatory therapies– Use of assistive devices to “unload” joints– Use of cognitive behavior therapy– Use of physical therapy and exercise therapy

• There are as yet no proven structure modifying therapies– Recent data regarding metalloproteinase inhibitors suggests some

benefit in patients with progressive disease (maybe)

BIOLOGIC MARKERS

HRQOL / UTILITY

PAINPAINPHYSICAL PHYSICAL FUNCTIONFUNCTION

PATIENT GLOBALPATIENT GLOBALIMAGING (≥1YR)IMAGING (≥1YR)

INFLAM-MATION

8%8%36%36%90%90%

OTHER Eg, Performance based Flares Time to Surgery Analgesic Count

MD GLOBALMD GLOBAL

STIFFNESS

Study Design

Arthritis assessments X X X

OA Knee Flare

Rofecoxib 25 mg qd

Week 6

Celecoxib 200 mg qd

Placebo

Week 3BL

BL = baseline

Weeks

Me

an

VA

S (

mm

) Placebo (n=60)Celecoxib 200 mg QD (n=63)Rofecoxib 25 mg QD (n=59)

30

40

50

60

70

0 3 60

*

*P < 0.02 both active treatments vs placebo

80

*

Patient’s Assessment of Pain

0

5

10

15

20

25

30

Celecoxib 200mg QD

Rofecoxib 25mg QD

Placebo

* *

*P<0.03 vs placeboWOMAC = Western Ontario and McMaster Universities Osteoarthritis Index

Me

an

imp

rove

men

t

fro

m b

ase

line

WOMAC Composite Scores at Week 6

PACES: Patient Preference Cross-over Trials Pincus etal Ann Rheum Dis 2004

PACES: Patient Preference Cross-over Trials Pincus etal Ann Rheum Dis 2004