BL 02-18-14 9-10AM OSTEOARTHRITIS-Janson_Hirsh Flashcards
Osteoarthritis (OA) defn.
- Heterogeneous disorder characterized by destruction (degeneration) of articular cartilage & proliferation (hypertrophy) of contiguous bone
OA & other arthritises
= end stage of all types of arthritis
Clinical features of OA
- localized joint tenderness
- joint pain improved w/rest
- stiffness <30 min, localized to involved joints
- decreased joint mobility
- relative preservation of function
- hypertrophic bony spurs (osteophytes)
- bony enlargment
- crepitance
- variable joint inflammation / instability
- NO systemic involvement
- Rarely symptomatic before age 40
Signs of OA - Specific pattern of deformity
- Heberden’s (DIP) & Bouchard’s (PIP) nodes - often inherited
- Squaring of 1st carpometacarpal joint
- Genu varus (bow-legged)
- Hallux valgus (bunion on big toe)
- Cervical & lumbar spine spondylosis (degenerative change)
Laboratory in OA - Labs in secondary OA
- uric acid
- iron, calcium. phosphate
- ESR, CRP
OA Clinical Syndromes- 6 Types
- Primary generalized OA
- Inflammatory/erosive OA
- Isolated nodule OA
- Unifocal large joint OA
- Multifocal large joint OA
- Unifocal small joint OA
Laboratory in OA - Synovial fluid analysis
Type I fluid
- 200-2000 WBCs
- 25% PMNs
- normal viscosity
Negative crystal exam
Normal glucose
Specific patterns of x-ray changes
- “Gull wing” changes in interphalangeal joints
- Medial compartment disease of the knee (wear out cartilage in knee joint)
- Horizontal osteophytes of spine
- Decreased joint space superiorly w/ relative medial preservation in hip
- Hallux valgus (bunion deformity of great toe) without other metatarsal disease
Epidemiology of OA - how common
- most common arthropathy
- advanced age is one of the strongest risk factors
- more OA found by X-rays than is symptomatic (X-ray correlates better w/symptoms in hip OA)
- found on autopsy in weight-bearing joints of ~100% of ppl by age 40
Laboratory in OA - Investigational labs
Cartilage degradation products in serum & joint fluid.
- Hyaluronic acid, fragments of aggrecan
- Type II collagen, & its breakdown products
- Cartilage oligomeric protein
Radiographic evaluation
- Loss of cartilage space
- Bony sclerosis & eburnation (hardening of bone surfaces b/c of cartilage loss)
- Cystic changes of subchondral bone
- Osteophyte formation
- Altered shape of bone
- Joint effusion – non-inflammatory
Epidemiology of OA - Males vs. Females
Overal frequency:
45 yrs = females predominate
Women have more severe disease & increased frequency of Heberden’s/Bouchard’s nodes
Epidemiology of OA - Occupational risks
- OA of the hips, knees, shoulders more frequent in miners
- OA of hands more frequent in weavers
- No increase in OA in pneumatic hammer drillers and in Finnish long distance runners
OA can be classified as…
- Primary, or idiopathic OA
- no known inciting event or disease - Secondary OA
- induced by known events/disease
Distribution of joints involved in OA
Highly variable:
- may involve 1 joint, esp. after trauma
- may be “generalized,” affecting PIPs, DIPs, & 1st carpometacarpal (CMC) joints
- Generally. primarily affects weight-bearing & heavily used joints
- Tends to spare ankle, wrist, shoulder, & elbow, unless significant trauma has occurred, or metabolic / inflammatory disease present
Gross pathology of OA
Joint in OA characterized by
- cartilage irregularities & “fissuring”
- hypertrophy of bone adjacent to the joint
Microscopic pathology of OA
Articular cartilage surface reveals frayed & disrupted collagen fibers.
- Chondrocyte cells first undergo clonal expansion (↑#) & the proteoglycan content of ECM ↓
- Subchondral bone has ↑ density
- Periarticular bone is hypertrophic
- Synovium has variable findings from normal areas, to areas inflamed & w/ cellular infiltrates
Normal cartilage - functions
- to allow joint movement w/ minimum friction
- to absorb some of the impact during normal joint loading
Epidemiology of OA - Sports risks
= in general, no increased risk (and exercise may be protective) in recreational participants.
= Chondrocytes may require some degree of mechanotransduction to maintain function
Epidemiology of OA - Other risks
- Trauma/previous injury is associated with OA
- Obesity - best correlation with OA of the knees and hands in women
Collagen in cartilage
- 50% of dry weight of cartilage
- 90% of the collagen is Type II (also, IX, X, XI)
- Forms rigid framework of articular cartilage, “holding in” hydrophilic matrix
Proteoglycans in cartilage
- Highly charged aggregates of glycosaminoglycans
- Bulk of ECM, contained w/in collagen fibrils
- Major components are chondroitin sulfate & keratin sulfate
- B/c of charge & tendency to aggregate, highly hydrophilic —> retain major component of cartilage, water
Matrix Proteins in cartilage
- Other proteins that contribute to ECM
- Most important proteolytic matrix metalloproteinases (MMP):
== Collagenase
== Gelatinase
== Stromelysin - Matrix also contains lots of tissue inhibitor of metalloproteinase (TIMP) —> controls proteolytic activity of these enzymes
Chondrocytes in cartilage
- -> Only 5% of total cartilage volume
- Synthesize all extracellular components
- Metabolically active
- Receive nutrition from synovial fluid or subchondral bone by diffusion through ECM
Water in cartilage
- Major component of cartilage
- 70% of the weight of intact cartilage
Cartilage in OA
Cartilage = main focus of pathology in OA
- Changes observed in OA cartilage represent final common pathway of abnormalities occurring in collagen, proteoglycans, matrix-proteins, & chondrocytes
- Primarily a degenerative process, BUT inflammatory mediators plays a significant role
Cartilage remodeling & OA
Cartilage normally remodels over time
Requires both:
- Destructive factors to degrade ECM components (MMPs)
- Constructive production of collage (mainly type II) & proteoglycans (aggrecan)
» Constructive factors
Local destruction of articular cartilage in OA
Many factors, cytokines, & inflammatory mediators are implicated as inciting local destruction of articular cartilage:
- focal mechanical stress
- pro-inflammatory substances released by chondrocytes & synovium
Focal mechanical stress involved in local destruction of articular cartilage in OA
- trauma, physical forces, joint instability, defects in proprioception, metabolic abnormalities, crystal disease
- -> can injur chondrocyte & cause degradative enzymes to be release –> collage fibrillation & matrix breakdown
- -> Type II collagen & its degradative products can be released
Normal cartilage - characteristics
- Highly hydrophilic nature of cartilage allows it to act like a sponge, with water squeezed out of cartilage during loading, followed by re-expansion during relaxation.
- Normal cartilage is avascular, and has no nerves
5 components of cartilage
- Collagen - 50% of dry weight
- Proteoglycans - bulk of ECM
- Matrix Proteins
- Chondrocytes - 5% of cartilage volume
- Water - 70% of intact cartilage weight
Chondrocyte/Synovium pro-inflammatory substances involved in local destruction of articular cartilage in OA
Cytokines & Inflammatory mediators --> promote progression of cartilage damage Include: - IL-1, IL-6, IL-17, IL-18 - TNF-alpha - Nitric oxide (NO) - Prostaglandins (PGs)
Interleukin-1 (IL-1) in OA
- –> promotes ECM degradation & decreases new matrix formation
- specifically, promotes degradation of type II collagen & aggrecan by stimulating chondrocytes to make MMP
- stimulates other mediators (PGE2, NO, IL-6)
- Plays pivotal role in sustaining inflammation & cartilage degradation
Tumor necrosis factor α in OA
- Behaves like IL-1 & works synergistically w/ it to damage cartilage
- Stimulates production of MMPs
Chondrocytes/Synovium also produce Inhibitor Cytokines:
- IL-4, IL-10, IL-13, & IL-1 receptor antagonist (IL-1Ra)
- -> ↓ production & activities of catabolic & proinflammatory cytokines in chondrocytes in vitro
- –> suppress cartilage destruction in vivo
- –> Transforming growth factor-beta (TGF-β) & insulin-like growth factor (IGF-I) implicated in maintaining cartilage by anabolic mechanism
Other factors promoting cartilage damage in OA
- Complement activation
- Adipokines
Nitric Oxide (NO) in OA
Produced by endothelial cells & chondrocytes
- -> catabolic effects on cartilage
- -> like IL-1, increases MMP production & inhibits proteoglycan synthesis
- as OA cartilage tries to repair itself, chondrocytes proliferate greatly
- NO seems to induce chondrocyte apoptosis, inhibiting this reparative response
Prostaglandins
= can have multiple effects on various cells in joint
Negative effects
- increased production & activation of MMPs (specifically stromelysin)
Complement activation in pathogenesis of OA
High expression & activation of complement in OA pt’s synovial fluid/tissue
Membrane attack complex on chondrocytes appears critical to OA development
- –> chondrocyte cell death or production of degradative enzymes & inflammatory mediators
- –> cartilage loss
Released / exposed cartilage ECM components may trigger complement cascade
Adipokines in OA
- cytokines mainly produced by adipose tissue
- may be linked to development of OA
- Obesity associated w/systemic low-grade inflam.
- ↑ Risk of hand OA in obese individuals (not explained by overloading of the joints)
Cartilage component levels during development of OA
Initially, water content increases in cartilage
- – Collagen-proteoglycan network weakens
- – Collagen fibers become weaker w/ looser “weave”
Proteoglycan content begins to decrease (in advanced OA, may be 50% or less of normal)
—> accompanied by increase in degradative enzymes
Chondrocytes initially increase in number, then in later stages of OA die
Development of OA on Gross morphologic level
- Cartilage surface becomes disrupted & fragmented with pits & ulcers.
- Bone may develop bare areas.
- Bone responds by making osteophytes, which may be capped by fibrocartilage
- Bone reparative processes may cause formation of type I collagen
Etiology of OA
- Unknown
- Several predisposing factors IDed
Genetic predisposing factors for OA
- Some forms of OA have genetic predisposition
- Recently demonstrated that point mutations in type II collagen gene can result in accelerated familial OA & chondrodysplasia.
- –> accounts for only a tiny % of cases of OA
Metabolic abnormalities in cartilage as predisposing factors for OA
Several metabolic diseases are associated w/ accelerated OA (mechanism unknown):
- hemochromatosis
- Wilson’s disease
- ochronosis
Direct chondrocyte toxicity + deposition of calcium pyrophosphate crystals in ECM may contribute to the disease process
Trama as predisposing factor in OA
In the form of:
- mechanical instability
- mechanical incongruity
- excessive load (obesity)
- denervation (loss of normal pain feedback)
Disruption of normal joint mechanics cause rapid development of OA
Postulated that trauma –> chondrocyte injury –> imbalance between anabolic & catabolic products of these cells (mechanotransduction) –> ECM degradation & eventual OA
IL-17 in OA
- produced by Th17 T-cells
- increases expression of IL-1
IL-18 in OA
- produced by macrophages
- induces IL-1 & TNF α production
Age as predisposing factor in OA
- 75% of persons over age 70 have OA
- uncommon under age 40
- May in part be associated w/age-related ↓# of chondrocyte in articular cartilage
Inflammatory joint disease as predisposing factor in OA
- Cartilage damage initiated by other processes may also result in development of secondary OA
<— RA, crystals, or infection
Types of treatment targets in OA
- Biomechanical or biochemical targets?
- Primary prevention? (reduce risk factors like obesity & repetitive activities)
- Secondary prevention? (prevent progression with disease modifying OA drugs - DMOADs)
- Tertiary treatment? (treat consequences of OA)
Obesity as predisposing factor in OA
- related to knee and hip OA, as well as to hand OA
Timing of Dx in OA
- B/c OA is defined by symptoms & radiographic changes, Dx not made clinically until very late (many years) after initiation of disease.
Psychosocial variables in OA
- Degree of pain perception (psychosocial) disproportionate to degree of true OA involvement
Intra-articular agents for OA
- Corticosteroids
- Hyaluronic acid to OA knee pain
Nutraceuticals for OA
- Most commonly glucosamine & chondroitin sulfate
Glucosamine = aminosaccharide component of glycosaminoglycans, hyaluronan, keratan sulfate & heparin sulfate
Physical modalities to prevent rapid cartilage loss
- ↓ Weight, if obese
- Modify activities & occupation
- ↓ Weight bearing load (canes, crutches)
- Assistive devices
- Physical therapy - gait instruction, strengthening
- Exercise may…
- –> improve general health
- –> modify risk factors in disease progression
- –> ↑ ROM & flexibility
- –> ↑ Endurance & Strength
- –> ↓ Fall risk
- –> May even be chondroprotective
Types of Medication for OA
- Topical agents
- Nonopioid analgesics (e.g., acetaminophen)
- Anti-inflammatory agents such as NSAIDs
- Opioid analgesics
- Nutraceuticals & alternative therapies
- Intra-articular agents
- Adjunctive therapy such as muscle relaxants
Surgery types for OA
- arthroscopic
- reparative
- reconstructive
- total joint replacement
Alternative therapies for OA
Used by over 80% of patients w/ OA Some have been formally studied w/out proven benefit, including: - Leech therapy - S-adenosylmethionine (SAMe) - Ginger extract - Avocado/Soybean Unsaponifiables - Acupuncture - Electromagnetic fields - Magnets
