Transcript Document
OSTEOARTHRITIS
Two Major Forms of
Musculoskeletal Pain
Articular
Degenerative: Osteoarthritis (OA)
Inflammatory: Rheumatoid Arthritis (RA), etc.,
Crystal-induced: Gout, CPPD
Other
Nonarticular
Fibromyalgia
Soft tissue trauma
Tendonitis, Bursitis, etc.
Arthritis Care: An Increasing Burden on Healthcare Resources
Prevalence
49.8
(19.2)
Millions of Cases in US
(% Population)*
50
40
28
(10.2)
30
20
10
15.8
(6.1)
2.1
(0.8)
0.3
(0.12)
0.6
(0.23)
0
*Data for 1993/94
†National Osteoporosis Foundation. www.nof.org. Dec 6, 2000.
The Arthritis Foundation Fact Book for the Media. Atlanta, Georgia. Arthritis Foundation; 1994:1–4.
Arthritis
43 Million people in the US have some form of
arthritis
2020 it is expected that 103 million people will be
effected
For approximately 3 million people in the US, the
primary cause of limitation of movement is
arthritis
Extent of Musculoskeletal
Diseases in United States
37.9 million people affected by arthritis
– 21 million with clinical signs and symptoms
of OA
– 2.1 million with RA
Data from 1990
Lawrence et al. Arthritis Rheum. 1998;41:778–799.
315 million physician visits/yr
8 million hospital admissions/yr
17 million people with activity limitation
1.5 billion days of restricted activity/yr
Data from 1990–1992
Yelin, Callahan. Arthritis Rheum. 1995;38:1351–1362.
5
Economic Impact of Musculoskeletal
Conditions in the United States
Direct Costs
12%
12%
5%
20%
46%
1%
4%
Direct medical costs
Indirect costs (lost wages)
Total costs
Physician
Hospital
Other provider
Drugs
Nursing home
Administrative
Other
$ 72.3 billion*
$ 77.1 billion
$149.4 billion (2.5% of GNP)
*In 1992 dollars
Data from Yelin, Callahan. Arthritis Rheum. 1995;38:1351–1362.
6
Osteoarthritis: AKA
Degenerative Arthritis
Osteoarthrosis
Old Age Arthritis
Degenerative Joint Disease
Wear and Tear Arthritis
DJD
Osteoarthritis
Definition
Slowly progressive deterioration of a
joint in which localized loss of
cartilage occurs in association with
subchondral sclerosis, osteophytosis,
cyst formation, and synovial
thickening
SOCIOECONOMIC IMPACT OF OA
Most common reason for physician visits in
people >55 years of age
Lost and limited work days
Impaired leisure activities
Co-morbidity: Heart disease, depression,
etc.
Cost = Billions
Normal vs OA Joint
Normal knee
Osteoarthritic knee
Thickened capsule
Capsule
Cartilage
Synovium
Cyst formation
Sclerosis in
subchondral bone
Fibrillated cartilage
Synovial hypertrophy
Bone
Osteophyte formation
11
Presentation
Symptoms
Pain: worse during the day—with activity or after
activity
Stiffness: Minimal in the morning (<30 min); gelling
after inactivity
Range of motion: decreased
Signs
Crepitus
Swelling—variable effusions
Restricted movement
Bony enlargement
Joint instability
Location & Prevalence of OA
80
Men
Prevalence of OA (%)
60
DIP
40
Knee
20
Hip
0
20
40
60
80
80
Women
60
DIP
40
Knee
20
Hip
0
20
40
60
Age (years)
80
Articular Cartilage
Integrity depends on a balance between degradation
and synthesis of extra-cellular matrix constituents
Homeostasis
Degradation
Synthesis
Pathogenesis of OA
Biomechanical
Matrix
synthesis
IGF-1
TGF-b
Chondrocytes
Matrix
degradation
Cytokines
Enzymes
N.oxide
Genetic
Loss of matrix integrity
Metabolic
OA
IGF = insulin-like growth factor; TGF = transforming growth factor
15
Articular Cartilage
A specialized connective tissue “organ” with a
highly ordered anatomic structure that is
avascular and aneural
A sparse chondrocyte population is embedded in
extra-cellular matrix composed predominantly of
water, proteoglycans, and type II collagen
The mechanical properties of articular cartilage
are attributable to the extra-cellular matrix
Normal Hyaline Cartilage
Cartilage Ultra-structure
Collagen fiber alignment assists distribution of
forces
Chondrocyte morphology varies within the tissue
Cartilage Structure
Proteoglycans
attach to hyaluronic acid via link
protein to form an “aggregate” or aggrecan
Aggrecan
interactions dampen compressive
loads
Type
II Collagen encapsulates aggrecan and
distributes forces, providing tensile strength and
resisting shear
Cartilage Structure
Osteoarthritis Biochemistry
Proteoglycan changes
Decreased () total proteoglycan (PG) content
hyaluronic acid (HA) content
aggregate size and aggregation of
proteoglycans
Collagen Changes
Ultrastructural changes in collagen
Increased water content
Chondrocyte response
division to form “clusters”
cellular hypertrophy
Osteoarthritis
Cytokines can promote degradation and inhibit
synthesis of extra-cellular matrix constituents
OA
Degradation
Synthesis
OA: Cartilage Changes
Osteoarthritic Cartilage
Radiographic Findings
Bony sclerosis
Joint space narrowing
Marginal osteophytes
Subchondral cysts
Malalignment
Osteoarthritis of hands
Osteoarthritis of Hands: X-rays
Osteoarthritis: Synovial Cyst
Osteoarthritis of the Knees
Osteoarthritis of the Knee
Subchondral bone
Femoral condyle
Patella
OA of the Hip
Pain often is located
deep in the groin and
radiates to the thigh
Check ROM
Osteoarthritis Cervical Spine
Narrowed
Neural
Foramina
Osteoarthritis Lumbar Spine
Diffuse Idiopathic Skeletal
Hyperostosis (DISH)
EPIDEMIOLOGY OF OA
Most common form of chronic arthritis
1:5 affected worldwide, increases with
age
>50% require medical therapy for pain
and disability
Risk Factors
Age
Female sex
Trauma
Obesity (micro-trauma)
Genetic or hereditary links
Neuromuscular dysfunction
Metabolic disorders
WEIGHT AND OA
Degree of Obesity
(Range of BMI)
Males
RR(95% CI)
Females
Normal (>20 to 25) 1.00
1.00
Overweight (>25 to 30)
1.69(1.03-2.80)
1.89(1.24-2.87)
Obese (>30 to 35)
4.78(2.77-8.27)
3.87(2.63-5.68)
Very Obese(>35)
4.45(1.77-11.18)
7.37(5.1510.53)
Am J Epidemiol 1988;128:179
Goals of Arthritis Therapy
Relieve pain/inflammation
Minimize risks of therapy
Retard disease progression
Provide patient education
Prevent work disability
Enhance quality of life and functional
independence
43
Drug Therapy Options in Osteoarthritis
Analgesics
NSAIDs (Rx, OTC), COX-2
Inhibitors
Topical agents
Intra-articular glucocorticoids
Intra-articular hyaluronan
Investigational agents
44
American Pain Society
Treatment of Chronic Pain in OA
Plus, as needed:
• Mild pain
• Little or no
inflammation
• Acetaminophen
Continued
pain?
Yes
• Moderate to severe
pain/inflammation
• COX-2–specific
inhibitor
Continued
pain?
Conduct GI risk-factor
analysis
• Nonpharmacologi
c interventions
• Glucosamine
• Tramadol
• Adjunctives
• Intra-articular
hyaluronic acid
• Surgical
intervention
• High risk
• Nonselective NSAID
plus PPI or misoprostol
• Not high risk
• Nonselective NSAID
Continued pain?
American Pain Society, 2002.
Yes
• Hyaluronic acid injection
for knee pain
• Glucocorticoid intraarticular injection for
other joint pain
ACR Osteoarthritis Guidelines
ACR Subcommittee on OA Guidelines. Arthritis Rheum 2000; 43: 1905-1915
ACR Osteoarthritis Guidelines
Nonpharmacologic Measures
Cornerstone of Therapy
ACR Subcommittee on OA Guidelines. Arthritis Rheum 2000; 43: 1905-1915
Nonpharmacologic Modalities
Patient education
Personalized social support
through telephone contact
Aerobic exercise program
Range-of-motion exercises
Assistive devices for
ambulation
Appropriate footwear
Bracing
Joint protection and energy
conservation
ACR Subcommittee on OA Guidelines.
Self-management
programs
Weight loss (if
overweight)
Physical therapy
Muscle-strengthening
exercises
Patellar taping
Lateral-wedge insoles
Occupational therapy
Assistive devices for
Arthritis Rheum activities
2000; 43: 1905-1915
of daily living
Physical Therapy
WOMAC
6 Minute Walk
Deyle, et al., Ann. Int. Med. 2000: 132; 173-81
ACR Osteoarthritis Guidelines
Nonpharmacologic Measures
Acetaminophen
for the relief of mild-to-moderate joint pain
ACR Subcommittee on OA Guidelines. Arthritis Rheum 2000; 43: 1905-1915
Acetaminophen
Symptomatic relief comparable to ibuprofen
Provides analgesia
Avoids adverse effects of NSAIDs, which are especially
worrisome in the elderly
Minimal risk of toxicity when chronic therapy is kept equal
to or below 4 gm per day
COX-3 & Acetaminophen
ACR Osteoarthritis Guidelines
Nonpharmacologic Measures
Acetaminophen
for the relief of mild-to-moderate joint pain
Topical Agents*
(methylsalicylate or capsacian)
*for those who do not wish to take systemic therapy
COX-2 Specific Agents
or
(celecoxib, valdecoxib or rofecoxib)
Intraarticular injections
(glucocorticoids or hyaluronan)
ACR Subcommittee on OA Guidelines. Arthritis Rheum 2000; 43: 1905-1915
Capsaicin
Derived from capsicum, i.e., chili peppers
Topical application
Mediated through Substance P receptors
Major effect is analgesia
Additional analgesics include tramadol,
narcotics
Corticosteroid Injections
Reserved for patients with an effusion or local
inflammation
Triamcinolone, hexacetonide, or betamethasone
Potential chondroprotective effects
Limited to 3-4 injections per year
Pond-Nuki dog model: corticosteroids reversed early
fibrillation
assist rehab
Potential deleterious effect on ligaments, tendon,
NSAIDs
Effects on chondrocytes, i.e., PG synthesis
In vitro: decreased by indomethacin
and sodium salicylate
increased by ibuprofen, sulindac, and
benoxaprofen
Ø from naproxen and diclofenac
Effects on cartilage
Degradation reduced by tiaprofenic
acid and possibly piroxicam
Progression of X-Ray s in knee OA
by indomethacin
• suppression of matrix synthesis and possibly
COX-3 Versus COX-2 &
COX-1
Pincus. Curr. Rheum. Reports. 2001; 3: 524-34
Considerations for Treatment
Selection COX-2 vs. NSAID?
Evaluation of risk factors for UGI complications
Age > 65 years
Comorbid medical conditions
Oral glucocorticoids
History of peptic ulcer disease
History of UGI bleeding
Anticoagulants
Smoking?
Alcohol consumption?
ACR Subcommittee on OA Guidelines. Arthritis Rheum 2000; 43: 1905-1915
COX-2 Inhibitors
Features
Selectively inhibit the COX isoform
upregulated with inflammation,
Inhibits production of PGE2 and IL-6
Reduce side effects of NSAIDs including GI
toxicity & platelet inhibition
Still has Renal effects, CV effects
Ulcer Complication/Symptomatic Ulcer
Rate
Non-Aspirin
Users
4
Celecoxib Long-term Arthritis Safety Study
Annualized Incidence (%)
P = 0.02
2.91
3
Celecoxib 400 mg BID
P = 0.04
Conventional NSAIDs
2
1.40
1.27
1
0.44
0
Complications
Complications and
Symptomatic Ulcers
Silverstein, et al. JAMA. 2000;284:1247–1255.
Rates of Complicated
Confirmed Events
VIGOR Trial
57%
reduction
Annual Incidence (%)
2.0
1.6
*
1.4
1.2
0.8
0.6
0.4
0
Rofecoxib
50 mg QD
*P 0.05
Bombardier, et al. N Engl J Med. 2000;343:1520–1528.
Naproxen
500 mg BID
RR for Hospital Admission for
GI Bleeds
4
3,5
Nsaid
Arthrotec
Vioxx
3
2,5
2
1,5
1
0,5
Celebrex
0
Mamdani,et.al.BMJ
2002;325:624-7
Controls
N=100,000
NSAID
5391
Arthrotec
5087
Vioxx
14,583
Celebrex
18908
Population
based
Canadian
% Patients Hospitalized
GI Safety
Time from Index Date (Days)
Mamdani M. BMJ 02
Recurrent Ulcer Bleeding in High
Risk Patients with Prior PUD
30
20
GI
bleeding
CV
15
HTN
25
10
edema
5
Celecoxib v.
Diclofenac/omeprazole
287 pts.(144c+143d/p)
Healing Endoscopic PUD
C: 4.9%(95%CI 3.1-6.7)
D+P: 6.4%(4.3-8.4)
Renal
fail
0
cel
d+PPI
Chan,et.al.NEJM2002;347:210410
Relationship Between Selective COX-2
Inhibitors and Acute Myocardial
Infarction
Solomon, et. al. Arth.&Rheum. 48;2003:S697
Retrospective analysis of two state sponsored
pharmaceutical benefit programs
Comparison of patients on rofecoxib, celecoxib,
NSAIDs, or none
54,475 patients included
941 on rofecoxib, age 82; 2140 on celecoxib, age
81
Matched for age, HTN, gender, AMI hx., duration
of rx.
Relationship Between Selective COX-2
Inhibitors and Acute Myocardial
Infarction
Solomon, et. al. Arth.&Rheum. 48;2003:S697
Rofecoxib vs. Celebrex: OR 1.24 (1.05-1.46)
Rofecoxib vs. no NSAID: OR 1.14 (1.00-1.31)
Celecoxib vs. no NSAID: OR 0.93 (0.84-1.02)
Rofecoxib >25mg vs. Celecoxib >200mg: OR
1.70 (1.07-2.71)
Rofecoxib <25mg vs. Celecoxib <200mg: OR
1.21 (1.01-1.44)
Relationship Between Selective COX2 Inhibitors and Acute Myocardial
Infarction
Solomon, et. al. Arth.&Rheum. 48;2003:S697
Rofecoxib vs. Celecoxib:
1-30 days OR: 1.39 (1.10-1.74)
31-90 days OR: 1.37 (1.09-1.71)
>90 days OR: 0.96 (0.73-1.26)
Rofecoxib vs. Naproxyn: OR: 1.17 (0.90-1.52)
vs. other NSAID: 1.17 (0.99-1.38)
Celecoxib vs. Naproxyn: OR: 0.95 (0.74-1.21)
vs. other NSAID: 0.95 (0.82-1.09)
Considerations for Treatment Selection
Evaluation of risk factors for reversible
renal failure in patients with intrinsic renal
disease
(Scr > 2.0 mg/dL)
age > 65 years
hypertension
congestive heart failure
use of diuretics
use of angiotensin-converting enzyme
ACR Subcommittee on OA Guidelines. Arthritis Rheum 2000; 43: 1905-1915
inhibitors
6-Week Elderly HTN*/OA†
Trials: Celecoxib vs Rofecoxib
Incidence of Clinically Meaningful BP Elevation
Trial
1P1 = 0.03
Trial
22
P < 0.01
5
16.
5
14.
9
% of Patients
15
12
11.2
9
6.9
6
NS
NS
3
2.3
2
3
1
0
0
SBP > 20
mm Hg
and > 140
mm Hg
Trial
22
4
% of Patients
18
Trial
11
SBP > 20
mm Hg
and > 140
mm Hg
*HTN = hypertension; †OA = osteoarthritis
1. Whelton, et al. Am J Ther. 2001;8:85-95.
2. Data on file. Searle, Skokie, IL.
1.5
2.2
1.3
Celecoxib
200 mg
QD
(n = 411)
Celecoxib
200 mg QD
(n = 549)
Rofecoxib
25 mg QD
(n = 399)
Rofecoxib
25 mg QD
(n = 543)
DBP > 15
mm Hg
and > 90
mm Hg
DBP > 15
mm Hg
and > 90
mm Hg
Annual Use of Non-narcotic Analgesics
and NSAIDs in the United States*
Non-narcotic analgesics:
22.2 million prescriptions1
Total sales of OTC analgesics:
$2.5 billion2
NSAIDs: 71.4 million
prescriptions1
*Data from 1997
1IMS; 2IRI InfoScan
70
Arthroscopic Surgery
Moseley, et al. New Eng. J. Med. 2002; 347: 81-8
THERAPEUTIC INTERVENTIONS
Symptom Modifying
Physiotherapy
Analgesia
NSAIDs
Surgery
Intra-articular
injections
Structure Modifying
MMP Inhibitors
Specific: None have
made it thru Phase III
Non specific: The
tetracyclines are in
testing
Growth Factor: IGFI
Dietary
Vitamin C
Glucosamine
Other Dietary Interventions
MSM: Unable to find any controlled trials
showing benefit. However, many
individuals note significant relief of pain
and swelling in hands with OA.
SAMe: Meta-analysis in 2002 found
efficacy equal to NSAIDs (Soeken, et. al.)
Recent Developments
Glucosamine & Chondroitin Sulfate
• Dose:
•
No FDA oversight
•
Brand to brand and intrabrand consistency are lacking
Building blocks of Glucosaminoglycans, namely aggrecan
•
Glucosamine 1500mg/day
Chondroitin 1200mg/day
Decrease synovial fluid IL-1b and collagenase
Clinical Evidence
Glucosamine
• Reginster, et al. Lancet. 2001; 357(9252):251-6
• 3 yr, d-b, p-c; studied joint space narrowing and WOMAC
Chondroitin
• Verbruggen, et al. Osteoarthritis & Cartilage. 1998; 6 Suppl A:378.
• 3year study in erosive OA of the hand: X-ray progression
Glucosamine-S & Symptom
Relief
Drovanti A, Bignamini AA, Rovati AL. Therapeutic activity of oral glucosamine sulfate in
osteoarthrosis: a placebo-controlled double-blind investigation. Clin Ther 1980;3:260-272.