OSTEOARTHRITIS UPDATE

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OSTEOARTHRITIS UPDATE
By prof.Dr. M.Elwy
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Osteoarthritis

• OA is still defined as a chronic irreversible
  degenerative disease of articular cartilage

Dieppe P. 1998
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Classification of OA

• Primary OA
• Most common form
• Is rare before age 40 years, prevalence increases
  with age
• Knee joint most often affected
• Genetic predisposition, particularly for hand
  arthritis
• Secondary OA
• Preceded by a predisposing disorder such as joint
  trauma
• Occurs in any joint

Solomon L. 1997
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Epidemiology

• Osteoarthritis (OA) is one of the commonest
  morbidities in older people, and the most common
  reason for restricted activity in their daily
  life.

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Prevalence and economic burden of musculoskeletal
disease

• More than 33 million people in the US (16 of the
  population) have a form of arthritis
• 28 million aged ?45 years
• prevalence is projected to increase to 18.2by
  2020 due to aging population
• Worldwide it is estimated that 9.6 of men and
  18.0 of women aged ?60 years have symptomatic
  OA
• 1.02.5 of Gross National Product (GNP) is spent
  annually on musculoskeletal disorders in the US,
  Canada, UK, France and Australia

CDC. 2001March L, et al. 1997 Woolf A, et al.
2003
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Prevalence of arthritis increases with age
Prevalence per 100 000
Prevalence per 100 000
30 000
3000
OA
RA
25 000
2500
Male
Female
20 000
2000
15 000
1500
10 000
1000
5000
500
0
0
04
1529
4559
7079
04
1529
4559
7079
514
3044
6069
³80
514
3044
6069
³80
Age group (years)
Age group (years)
Woolf A, et al. 2003
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Disability burden of musculoskeletal diseases OA
Ischaemic heart disease
Cerebrovascular disease
Total musculoskeletal disease
OA
HIV/AIDS
COPD
Liver cirrhosis
Asthma
RA
0
2
10
6
8
4
Disabilityadjusted life years (millions)
Reginster J, et al. 2002
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Risk factors for primary OA
Old age
Obesity
Gender
Occupation
Bone injury
OA
Family historyGenetics
Joint injury
Trauma
Jointdysplasia
Solomon L. 1997
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Gross appearance Of OAK
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• How does that occur without previous obvious
  trauma or disease
• In
• Primary OA
• ???????????????????????

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Anatomy of a normal synovial joint
Muscle
Bone
Capsule Ligaments hold thebones together
Cartilage Protects theend of the bone
Synovial fluid Lubricates thejoint capsule
Synovium Secretes thesynovial fluid
Tendon
Dieppe P. 1998
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Normal Articular cartilage components and
structure
Collagen and proteoglycanaggregates provide
tensile strength, elasticity and recoil
Chondrocytes regulate the synthesis and
degradation of cartilage by secreting enzymes
Tide mark separates articular cartilage from
calcified cartilage
Bone
Area of detail
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Articular cartilage in action
No load
Light load
Heavy load
Rebounding
Cartilage
Unaffectedcartilage
Lightcontact
Cartilagedistortion
Cartilageand bonerebound whenweight
isremoved
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Characteristics of OA
OA joint
Normal joint
Cartilage Pitted and frayed surface Loss of
elasticity Cartilage may wear away completely
Thickeningof capsule
Bone ends thicken Bony outgrowths (osteophytes)
form Bone fragments may float in the joint
space Fluid filled cysts may form in the bone
Modest, patchychronic synovitis
Dieppe P. 1998
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Articular cartilage in OA
Collagen fibre structure is altered and the
number and quality of proteoglycan aggregates
decreases
Erosion
More chondrocytes are produced resulting in an
imbalance in the synthesis and degradation of
cartilage components
Cartilage surface cracks and erodes.Small
fragments break off into synovial
fluid Eventually the bone becomes exposed
Bone
Area of detail
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Softening Stage
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Fibrillation Stage
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Fragmentation Stage
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In osteoarthritis and inflammatory arthritis

• the degeneration of the extracellular matrix far
  exceeds its synthesis. The extracellular matrix
  of cartilage wears away, exposing articular
  cartilage and, eventually, bone.

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Cartilage Loss

• Cartilage loss is the hallmark of established OA,
  and 60 of cartilage is lost by end-stage knee
  OA.
• Cartilage loss is of the order of 5 per annum in
  established knee OA and is a predictor of knee
  replacement.

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Cartilage Loss

• However, relatively little is known about the
  determinants of cartilage loss.

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• the cartilage changes are largely dependent on
  probably genetic factors
• 1. baseline differences in cartilage volume,
• 2. tibial bone area
• 3. BMI and
• 4. knee pain,
• 5. decrease in physical fitness

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• The two main constituents of the cartilaginous
  extracellular matrix are a type II collagenrich
  collagenous network, which provides tensile
  strength, and a cartilage-specific proteoglycan
  called aggrecan, which is highly hydrated and
  thereby allows cartilage to resist a compressive
  load

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• Under physiologic conditions, this
  cartilaginous extracellular matrix is constantly
  remodeled
• through degradation followed by the
  synthesis of
• collagen and aggrecan to maintain the integrity
  of cartilage.

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Aggrecan

• Aggrecan is the major proteoglycan in cartilage,
  endowing this tissue with the unique capacity to
  bear load and resist compression.

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Aggrecan

• The loss of aggrecan is the primary event leading
  to the destruction of cartilage, and so an
  understanding of how aggrecan is normally
  degraded and whether this process can be
  forestalled is critical to preventing
  osteoarthritis.

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• In arthritic cartilage, aggrecan is degraded by
  one or more 'aggrecanases'

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Aggrecanases

• These are enzymes comprising the ADAMTS (a
  disintegrin and metalloproteinase) family of
  proteinases.

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Aggrecanases

• Aggrecanases are key matrix-degrading enzymes
  that act by cleaving aggrecan at the
  Glu373-Ala374 site

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Aggrecanases

• The two key aggrecanases are
• aggrecanase-1 and
• aggrecanase-2

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Aggrecanases

• Although ADAMTS4 and 5 are expressed in joint
  tissues, and are known to be efficient
  aggrecanases in vitro, the exact contribution of
  these two enzymes to cartilage pathology is
  subject to intense research.

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PGs OA

• In vitro studies confirm that mechanical load
  is a potent regulator of matrix metabolism, cell
  viability, and the production of proinflammatory
  mediators such as nitric oxide and prostaglandin
  E2

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PGs OA

• A major role of prostaglandin E2 (PGE2)
• in the pathogenesis of OA is supported by in
  vitro data, which show that chondrocytes isolated
  from patients with OA produce 50-fold more PGE2
  than chondrocytes from patients without OA.

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PGs OA

• High concentrations of prostaglandins can inhibit
  collagen synthesis, and the inhibitory effects of
  interleukin 1 (IL-1) on collagen transcription
  may be mediated in part by prostaglandins.

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PGs OA
Prostaglandins also have significant effects on
osteoclasts and osteoblasts, participating in the
regulation of bone generation and resorption.
Degradation of the joint may also result from
prostaglandin-stimulated release of matrix
metalloproteinases (MMPs).
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Cytokines
Mechanical Stress
Trauma Obesity Altered loading
IL1, IL6 IL10, IL17 TNF-a, IFN-?
Cellular COX Activation Cellular
NOS2 Activation
NO
PGE2
O2
ONOO-, NO2, etc.
Inflammation, Cartilage degradation In ??? knees
with excessive ADAMTS5
Guilak Clin Orthop, Vol 423. June 2004. 17-26
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Aggrecanases

• ADAMTS5 is the major aggrecanase in mouse
  cartilage, both in vitro and in a mouse model of
  inflammatory arthritis. ADAMTS5 may be a suitable
  target for the development of new drugs designed
  to inhibit cartilage destruction in arthritis,
  although.

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Aggrecanases

• further work will be required to determine
  whether ADAMTS5 (aggrecanase 2) is also the major
  aggrecanase in human arthritis

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Aggrecanases

• ADAMTS1, 8 and 9 have weak aggrecan-degrading
  activity. However, they are not thought to be the
  primary aggrecanases

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Aggrecanases

• aggrecanase-1 and -2 are differentially regulated
  in FLS (fibroblast-like synoviocytes) . Both are
  constitutively expressed, but aggrecanase-1 is
  induced by cytokines, especially TGF- . In
  contrast, aggrecanase-2 protein may be regulated
  by a post-translational mechanism in OA and RA
  ST. Synovial and FLS production of aggrecanase
  can contribute to cartilage degradation in RA and
  OA.

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Aggrecanases

• ADAMTS4 (aggrecanase-1), a secreted enzyme
  belonging to the ADAMTS (a disintegrin and
  metalloproteinase with thrombospondin motifs)
  gene family, is considered to play a key role in
  the degradation of cartilage proteoglycan
  (aggrecan) in osteoarthritis and rheumatoid
  arthritis

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Aggrecanases

• one particular member of the aggrecanase family,
  aggrecanase 2 (ADAMT5), plays a crucial role in
  this destructive process.
• Genetically engineered mice that lacked a part of
  one such enzyme, aggrecanase-2
• were largely protected from cartilage
  destruction.

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Future Research Gene Therapy

• mutations in a single gene can halt cartilage
  degradation.
• Theoretically it might be possible to fight
  arthritis by developing drugs designed to inhibit
  the human form of aggrecanase 2.

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Signs and symptoms of OA

• Signs
• Loss of joint space
• Joint grinding/grating
• Bony outgrowths (osteophytes)
• Joint deformities e.g. Heberdens nodes

• Symptoms
• Use-related joint pain
• Joint stiffness after periods of inactivity
• Loss of joint movement/difficulty performing
  certain tasks
• Joint locking/giving way
• Feeling of instability
• Restricted/painful movements

Oxford Handbook of Clinical Medicine. 1998
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Joint involvement in OA

• Common
• Knee
• Hip
• Fingers
• Spine

• Less common
• Elbow
• Shoulder
• Wrist
• Ankle

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Knee deformity in OA
Sciencephoto.com
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Finger deformities in OA

• Deformities occur at
• The base of the thumb (Bouchards nodes)
• The middle joint of a finger (Bouchards nodes)
• The finger tip(Heberdens nodules)

Heberdens nodulesin a patient with OA
Sciencephoto.com
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Management

• Improve joint care through rest and exercise.
• Maintain an acceptable body weight.
• Control pain with medicine and other
  measures.
• Achieve a healthy lifestyle.

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Wisdom !!!

• Just as arthritis is not one condition, no
  single treatment is likely to yield satisfactory
  results.
• A systemic approach targeting pro-inflammatory
  cytokines, the dual inflammatory pathways and
  cartilage destruction should more effectively
  address the multifaceted nature of the host of
  conditions that are known as arthritis.

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Myths Truths about OA

• Myth
• Once you get arthritis, you just have to live
  with it
• Truth you can manage your arthritis
• In many ways live comfortably

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Myths Truths about OA

• Myth
• No cure is available for most forms of arthritis
• Truth
• However, early diagnosis management can help
  reduce impact of arthritis

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Exercices
Suppress the signal transduction pathways of
proinflammatory/catabolic mediators
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Even Fitness Performance Can be Genetically
Manipulated In the not-so-far future !!
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OA Medications !

• NSAIDs
• Nutritional Therapies
• Non Traditional therapy
• Future Therapies

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Patient Perspectives !!!
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Doctor Perspectives !!!
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Surgery

• Osteotomies
• Arthroscopy
• Resurfacing procedures
• Joint replacement

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Total Knee Arthroplasty

• Absolute Contraindication
• Active or Recent Infection
• Relative Contraindications
• Very Young, Very Active
• Neuropathic Joints
• Unsatisfactory Mental State

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Overall Results of TKR

• 90 good or excellent Pain Relief
• Fair to Good Improvement of function

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Complications of TKR

• Malalignment loosening
• Soft tissue imbalance
• Patellar problems frs. subluxation
• Infection
• Wear material design

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Thank You