الرحيم الرحمن الله بسم

علما ) زدنى رب ( وقل

العظيم الله صدق

OsteoarthritisDr. Abdallah El-Sayed AllamMSc of Physical Medicine, Rheumatology and Rehabilitation. Faculty of Medicine. Tanta University. EgyptMSK US fellowship. National Taiwan University Hospital. Taiwan

Definition 1

Epidemiology & classification 2

Aetiopathogenesis 3

Clinical picture4

Diagnosis5

Differential diagnosis6

Treatment, Updates & Guidelines 7

Definition

OsteoarthritisOsteoarthrosis

OA is a progressive, age-related disease characterized by progressive articular cartilage loss, appositional new bone formation (osteophytes) and sclerosis of the subchondral trabeculae and growth plate. Synovitis is often observed and is considered to be secondary to the changes in the joint.

Epidemiology

Classification

Aetiopathogenesis

The relationship between aging, joint damage, and

inflammation is still unclear. A high prevalence of US

inflammatory abnormalities in the knee joints of a

normal aged population. These data suggest a

substantial contribution of inflammation in progressive

impairment of joint function with age.

Goldring,2000

Risk factors (genetic, age, sex, occupation…..etc

Chondrocytes

IL 1

MMP13

Synovium

Matrix degradationJoint destrucion

Synovitis

Osteoclasts

BMLs

FGFR1FGFR3 FGFR1FGFR3

MMP13& ADAMTS5

Normal OA

Subchondral Bone?

Šimanek, et al 2005

• Subchondral circulation• Hairline microcracks in subchondral bone• Microfractures across tidemark• Synovial fluid

Brandt, et al 2003

• BMLs

• Venous Hypertension

• Arteriosclerosis

• Vascular channels

• Fractures

• Sclerosis

Synovium?

Crystals?

OA Crystals

Caus

e Result

Association

Plica?

Infra-patellar pad of fat?

miRNA

MicroRNAs (miRNAs) are endogenous, noncoding, single-stranded RNAs of 19–25 nucleotides in length.

3 miRNAs were associated with the need for hip

or knee replacement: miR-454, miR-885-5p, and

let-7e.

The most promising single miRNA was let-7e

"The lower the levels of let-7e, the higher the

likelihood of needing surgery for osteoarthritis of

the knee or hip."

Histopathology changes

ONE FAMILY WORKSHOP5/10/2014

Mechanism and sourcesOf pain

Neuropathic

-synovium-saphenous nerve

Clinical picture

Symptoms :Pain Stiffness Instability CrepitusSwelling

CLINICALPRESENTATION

Signs :Antalgic gaitDeformity Swelling Tenderness Crepitus

Clinical

1

Symptoms and signs

2

Laboratory

3

Radiologic

-ESR-SynovialFluid analysis

-X-ray-US-MRI

• Criteria

• Plain Xray

• MRI

• MSK US

Criteria

Serology

Plain Xray

Medscape CME

MSK US

DD

e OA e RA+ + CP

- + RF

- + ACPA

+ 14-3-3-ŋ

+ bone-derived substance hydroxyproline (Hyp)

Pitfalls

TTT

Education Life style modification

Mild

Severe

Dieppe, et al 2005

Surgery

Local injection Pharmacologic

Non pharmacologic

Life stylemodification

Knee and Hip

Exercise therapy

Balancing the minimal risk of

exacerbating early OA against the

benefits (pain relief, fitness and weight

control, and general health benefits).

1- Muscle mass is proportional to medial tibial

cartilage volume.

2- It increases intra-articular interleukin-10

levels, which is anti-inflammatory and

chondroprotective .

Physical Exercise of immune cells or skeletal

muscle cells increases plasma Brain Derived

Neurotrophic Factorimprovement of pain and

function in OA and chronic inflammatory conditions

1. Urge patients to walk, walk, and walk,

aiming for 150 minutes a week at moderate

intensity (3 miles/hour or 150 steps/minute),

White said.

2. Recommend using a pedometer.

3. Aim for 6,000 steps a day, the breakpoint that

divides those who lose physical function from those

who don’t.3, 4 This may entail walking only an extra 10

minutes every day, (Most adults over age 60, even

those with OA, ordinarily walk 4,000 to 5,000 steps per

day. At 150 steps a minute a mere 10 minutes could

easily make up the difference.)

4. To reduce the risk of joint damage, you

might suggest that patients take breaks

inbetween walking periods

5-Patients with knee OA who have been

regular runners probably don’t harm

themselves by continuing to run, may not be

advisable for patients with severe OA,

running does not appear to increase the

risk for incident knee OA in healthy people,

either.

Ultrasound therapy

Mechanism of action :

- Deep heat generated from ultrasound therapy

provides analgesia, decreases muscle spasm,

increases collagen extensibility and accelerates

metabolic processes.

- Pain relief may occur as a result of the activation of A

alpha- and A beta-mechanoreceptors that inhibit

nociceptive transmission in A delta- and C-fiber pathway

Pharmacologic therapy

Analgesics

NSAIDs

Pain management

Kehlet H, et al. ( 1993)

Antidepressants:

• are now recognised to have an analgesic effect in chronic pain independent of their antidepressant properties. They have been used successfully in neuropathic pain, as in diabetic neuropathy or post-herpetic neuralgia. They may be of benefit in other conditions, such as chronic low back pain, OA, RA and fibromyalgia.

Fishbain D.( 2000)

Anticonvulsants:• Gabapentin and pregabalin are anticonvulsant drugs

that have been used to treat neuropathic pain. They modulate the function of voltage-gated calcium channels, thereby reducing calcium entry into the presynaptic terminal. These compounds chiefly reduce calcium influx through presynaptic P/Q-type calcium channels, which are primarily activated under pathophysiologic conditions; however, most calcium influx is through N-type calcium channels. Pregabalin also appears to reduce the release of substance P, a key inflammatory mediator associated with pain in OA

**Vanegas, et al 2000 ***Fehrenbacher, et al 2003

*Joshi GP.( 2005)

Chondro-protectives

DMOADs

ONE FAMILY WORKSHOP5/10/2014

DiacerinDIACERIN

IL-1

Activates monocytes/ macrophages

Induces fibroblast proliferation

Activates chondrocytes

Activates osteoblasts

Inflammation Synovial pannus formation

Cartilage breakdown

Bone resorption

Mahajan, et al (2006)

Due to the risks associated with severe diarrhoea, diacerein is no longer recommended in patients aged 65 years and above.

50 mg daily instead of 100 mg and should stop taking diacerein if diarrhoea occurs.

must not be used in any patient with liver disease or a history of liver disease,.

Bisphosphonates

• They inhibit osteoclastic bone resorption by causing the osteoclast to internalize the bisphosphonate and inducing apoptosis by inhibition of intermediate enzymes in the mevanolate pathway. Russell, et al 1999

• a chondroprotective effect. Podworny et al 1999• metalloproteinases (MMPs), including MMPs 1, 2, 8,

9, 12, and 20. Valleala, et al (2003)• interfere with vascular endothelial growth factor

(VEGF), fibroblast growth factor (FGF), and angiogenesis. Green, et al (2002).

Rationale for Bisphosphonates in Human Osteoarthritis

• Similarities exist between osteoarthritic and osteoporotic bone. Bone mineral density (BMD) in subchondral regions of the knees in OA patients, whether or not they have osteoporosis (OP), is significantly reduced in OA Patients. Karvonen, et al 1998.

• The changes in subchondral bone stiffness and density may diminish structural support for the overlying cartilage. Kamibayashi, et al 1995.

• MRI has shown that lesions described as bone marrow “edema” with an increased signal on fat-suppressed T2-weighted images are associated with OA pain. Felson, et al 2001 These lesions have also been associated with progression. Felson, et al 2003

• So, agents directed toward subchondral bone have slowed progression of bone marrow lesions. Bingham, et al 2004

Matrix Metalloproteinase Inhibitors

• A number of MMP inhibitors have been developed that

have been tested in various animal models of arthritis.

An inhibitor of the collagenases (MMP-1, -8, and -13)

decreased cartilage degradation with IL-1 in bovine

cartilage explants and also in animal models of

inflammatory arthritis Lewis, et al 1997 Interestingly, but

perhaps not surprisingly, while cartilage damage was

decreased, inflammation was not significantly affected.

Bronner, et al 2007

• Tetracyclines and their derivatives have been demonstrated to inhibit collagenases including MMP-2 and -9 Greenwald , et al 1998

• Tetracycline derivatives have activity that is independent of their antimicrobial effects in periodontal disease Golub , et al 1998

• Doxycycline decreases collagenase and gelatinase production from OA cartilage explants Smith, et al 1998

Calcitonin

• Calcitonin not only decreases markedly the enhanced turnover of osteoarthritis subchondral bone trabeculae but also reduces significantly the severity of cartilage osteoarthritis lesions. Finally, calcitonin is analgesic to bone and has been reported to be superior to naproxen in relieving osteoarthritis knee pain. Manicourt, et al (2005).

Statins

• it is possible that these agents act on the intrinsic cholesterol content in cell membranes.

• interfere with leukocyte attachment to endothelial cells. This prevents the subsequent escape by the endothelial cell from the vasculature.

• Inhibition of the formation of focal adhesion• complexes (foci for transmembrane adhesion

molecules) is thought to be due to the effect of statins on members of the Rho family.

• interfere with the chemoattractant action of monocyte chemotactic protein-1 (MCP-1).

• The ability of statins to reduce the expression of a number of inflammatory cytokines is likely due to their inhibition of NF-B activation in monocytes or endothelial cells that have been exposed to inflammatory stimuli. NF-B is a transcriptional regulator of more than 40 inflammatory genes.

• It has been proposed that lthe progression of OA to advanced states is driven by atheromatous vascular disease. They support the hypothesis that subchondral bone ischaemia contributes to joint degeneration. So, statins can slow progression of established OA.

Local steroids

Beneficial or harmful ???????????

Hyaluronic acid

Mechanism of action

•Viscosupplementation: allow synovial fluid in joints

to behave differently depending on the load (ie, with

low joint stress, hyaluronans are highly viscous, but

when joint stress increases, hyaluronans become more

elastic and absorb energy more efficiently). This

flexible functioning is beneficial in an osteoarthritic

joint.

• Chondroprotective effect is due to preservation of

mitochondrial function and amelioration of mitochondria-

driven apoptosis.

•The suppression of inflammatory cytokine activity within

the joint.

•Relief of pain: due to supression of inflammation of the

knee joint that influences excitability of nociceptors of

articular nerves.

•Increases proprioception.

Updates

1. Synovitis pain and degeneration and

flares decreased function

2. MTX anti-inflammatory

suppression of synovitis reduction of

pain improvement of function

Gene therapy

Stem cell therapy (Mesenchymal stem cells)

Ozone Therapy

(A) Possible inactivation and inhibition of the release of proteolytic enzymes and of proinflammatory cytokines.

(B) Stimulation of the proliferation of chondrocytes (probably via H2O2) and fibroblasts, with increased synthesis of matrix and possibly of articular cartilage. Induction of the synthesis of antioxidant enzymes (SOD, GSH-Px and catalase) may be a crucial event as an adaptive response to COS and to ozone. That is the reason why I would start infiltrating ozone at low doses.

Bocci V(2010)

(C) Release of bradykinin and synthesis of inflammatory PGs is probably inhibited, with reabsorption of oedema and pain relief.

(D) An increased release of IL-1 soluble receptor or of other soluble receptors and antagonists able to neutralize proinflammatory cytokines such as IL-1, IL-8, IL-12, IL-15 and TNF-alpha.

(E) Conversely the release of immunosuppressive cytokines, such as TGF-β1 and IL-10, may inhibit inflammation.

Bocci V(2010)

Fish Oil

• typical dose among users is 1 mL of fish oil per day, which consists of 0.3 g of eicosapentaenoic acid (EPA) and docosahexanoic acid (DHA), which is considerably below the anti-inflammatory dose of 10 mL, or at least 2.7 g of EPA/DHA.

• 4.5 g EPA/DHA per day• 0.45 g EPA/DHA per day.

• "The unanticipated finding of better pain and function in the low-dose fish oil/sunola group requires further investigation," the researchers concluded.

Bone marrow aspirate concentrate (BMAC): A newer option than platelet-rich plasma (PRP), this product rich with blood precursors is already being used to heal damaged cartilage in racehorses.

Acetaminophen

IA steroids

HCQ for Mild/Moderate Hand OA

• Off-label for the relief of osteoarthritis (OA) of the hand, appears not to be effective, at least for mild to moderate cases.

Guidelines

Thank You