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 *8000 if subthreshold included. Adapted from Marder WD. Arthritis Rheum. 1991;34:1209–1217.

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

Structure of Cartilage

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

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

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

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 3

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 5

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 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

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

Patient’s Assessment of Pain 80 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

WOMAC Composite Scores at Week 6 30 * * 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

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

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