Osteoarthritis: Etiology, Pathogenesis and Treatment Considerations

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
• gt75 of people over the age of 75 have x-ray
  evidence of disease
• gt 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. 19913412091217.
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
• 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/Bouchards 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
• Heberdens nodes at the DIP joints
• Bouchards nodes at the PIP joints
• Often have squared first CMC joint due to
  osteophytes at that joint

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
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 - 1995



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
8
36
90
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
Week 6
Week 3
BL
Arthritis assessments X X X
BL baseline
29
Patients Assessment of Pain
80
70
Placebo (n60)
Celecoxib 200 mg QD (n63)
Rofecoxib 25 mg QD (n59)
60
50
Mean VAS (mm)


40
30
0
0
3
6
Weeks
P lt 0.02 both active treatments vs placebo
30
WOMAC Composite Scores at Week 6
30


Mean improvement from baseline
Celecoxib 200mg QD
Rofecoxib 25mg QD
Placebo
Plt0.03 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
33
(No Transcript)