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

2. 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

3. Prevalence of Rheumatic Disorders
*8000 if subthreshold included.
Adapted from Marder WD. Arthritis Rheum. 1991;34:1209–1217.

4. The 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

5. Structure of Cartilage

6. Risk Factors Genetics Trauma Overuse syndromes Post-infectious Obesity
Abnormal components of the joint as an organ
Abnormal range of motion
Congenital anomolies
Trauma
Overuse syndromes
Post-infectious
Obesity

7. 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

8. 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

9. Conceptual Model of OA Biochemical changes/ cells and tissue
Structural changes
Pain and other signs and symptoms
Functional limitation
Reduced quality of life
Surgical replacement

10. OA: Pattern of Joint Involvement
Neck
Lower Back
DIPs
Hips
CMCs
Knees
PIPs
Base of big toe

11. 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”

12. 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

13. 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 3

14. 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

15. Radiographic Features of the Knee in OA
Joint space narrowing
Marginal osteophytes
Subchondral cysts
Boney sclerosis
Malalignment
Joint space
narrowing 5

16. 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”?)

17. 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

18. 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)

19. 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.

20. 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.

21. 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

22. 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

23. 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

24. 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

25. 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

26. 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)

27.    BIOLOGIC MARKERS HRQOL / UTILITY PAIN PHYSICAL FUNCTION
PATIENT GLOBAL
IMAGING (≥1YR)   
INFLAM-MATION
STIFFNESS
90%
36% 8%
MD GLOBAL
OTHER Eg, Performance based
Flares
Time to Surgery
Analgesic Count

28. Study Design Placebo OA Knee Flare Celecoxib 200 mg qd
Rofecoxib 25 mg qd BL
Week 3
Week 6
Arthritis assessments X X X
BL = baseline

29. Patient’s Assessment of Pain80 70
Placebo (n=60)
Celecoxib 200 mg QD (n=63)
Rofecoxib 25 mg QD (n=59) 60 50
Mean VAS (mm) * * 40 30 3 6
Weeks
*P < 0.02 both active treatments vs placebo

30. WOMAC Composite Scores at Week 630 * * 5 10 15 20 25
Mean improvement from baseline
Placebo
Celecoxib 200mg QD
Rofecoxib 25mg QD
*P<0.03 vs placebo
WOMAC = Western Ontario and McMaster Universities Osteoarthritis Index

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

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