CURRICULUM VITAE

Nama : Natsir Akil

RIWAYAT PENDIDIKAN
1992 Dokter Umum Universitas Hasanuddin
2002 Internist Universitas Hasanuddin
2008-2010 PENDIDIKAN KONSULTAN REUMATOLOGY
FKUI

RIWAYAT PEKERJAAN
1992-1995 : PUSKESMAS Sumarorong Kabupaten Polmas
Sulawesi selatan
1996 : RSUD Ampana Kabupaten Posos Sulawesi
tengah
2002 2009 : Staf RSUD Dr.H.Soemarno Sostroatmojo
Tanjung Selor Kabupaten Bulungan Kaltim
2010-sekarang : Staf SMF Penyakit Dalam RS kanujoso
Djatiwibowo Balikpapan Kaltim

ORGANISASI
IDI, PAPDI, IRA



Natsir Akil
 Osteoarthritis (OA)
The most prevalent
joint disease and a
leading cause of
disability in older adults
OA related pain and
limitation of activity are
one of the most
common causes for
adult consultation in
primary care.
Osteoarthritis of the Knee
 Normal Cartilage
Avascular,
alymphatic and
aneural tissue
Smooth and
resilient
Allows shearing and
compressive forces
to be dissipated
uniformly across the
joint
 Structure of Normal Cartilage
Chondrocytes are responsible for metabolism of ECM
They are embedded in ECM and do not touch one
another, unlike in other tissues in the body
Chondrocytes depend on diffusion for nutrients and
therefore the thickness of cartilage is limited
Extracellular matrix is a highly hydrated combination
of proteoglycans and non-collagenous proteins
immobilized within a type II collagen network that is
anchored to bone
 Water
ECM Proteoglycan
Collagen

Normal
cartilage

Chondrocyte
Chondrocytes embedded in ECM, electron
micrograph
 Function of Normal Cartilage
Critically dependent on composition of ECM
Type II (IX&XI) provide 3D fibrous network
which immobilizes PG and limits the extent of
their hydration
When cartilage compresses H2O and solutes
are expressed until repulsive forces from PGs
balance load applied
 Function of Normal Cartilage
On removing load, PGs rehydrate restoring
shape of cartilage
Loading and unloading important for the
exchange of proteins in ECM and thus to
chondrocytes
Chondrocytes continually replace matrix
macromolecules lost during normal turnover
 Normal catabolism of cartilage
Chondrocytes secrete degradative proteinases which
are responsible for matrix turnover
These include: collagenases (MMP-1), gelatinases
(MMP-2), stromolysin (MMP-3), aggrecanases
Normal cartilage metabolism is a highly regulated
balance between synthesis and degradation of the
various matrix components
 OA cartilage

Synthesis

Degradation
 OA cartilage
The equilibrium between anabolism and
catabolism is weighted in favor of degradation
Disruption of the integrity of the collagen
network as occurs early in OA allows
hyperhydration and reduces stiffness of
cartilage
 Mechanisms responsible for
degradation
Catabolism of cartilage results in release of
breakdown products into synovial fluid which
then initiates an inflammatory response by
synoviocytes
These antigenic breakdown products include:
chondrointon sulfate, keratan sulfate, PG
fragments, type II collagen peptides and
chondrocyte membranes
 Mechanisms responsible for
degradation
Activated synovial macrophages then recruit PMNs
establishing a synovitis
They also release cytokines, proteinases and oxygen
free radicals (superoxide and nitric oxide) into
adjacent and synovial fluid
These mediators act on chondrocytes and
synoviocytes modifying synthesis of PGs, collagen,
and hyaluronan as well as promoting release of
catabolic mediators
 Cytokines in OA
It is believed that cytokines and growth factors
play an important role in the pathophysiology
of OA
Proinflammatory cytokines are believed to
play a pivotal role in the initiation and
development of the disease process
Antiinflammatory cytokines are found in
increased levels in OA synovial fluid
 Cartilage
IGF-1 Matrix
BMPs synthesis
IL-4 IL-1Ra PGE2
IL-10 sTNF-R
IL-6
LIF IL-13
IL-17 IL-8
OSM
IL-1 IL-18
TNF-

Cartilage
Matrix
degradation

Goldring MB. Textbook of Rheumatology. 8th ed., 2009, 37-61

 TNF- and IL-1
Induce joint articular cells to produce other
cytokines such as IL-8, IL-6
They stimulate proteases
They stimulate PGE2 production
Blocking IL-1 production decreases IL-6 and IL-
8 but not TNF-
Blocking TNF- using antibodies decreased
production of IL-1, GM-CSF and IL-6
 Obesity, Aging
Developmental
and anatomic Genetic and
abnormalities metabolic
Bony Stresses Cartilage disease
remodeling and Abnormal abnormal
micro fracture Inflammation

Loss of joint Normal Administration

stability cartilage of toxins
Immune
Trauma response

Theory A Theory B
Biomaterial failure Cell injury
collagen network Increase of degradative responses
fracture
Inhibitors reduced
Proteolytic enzymes increased
Proteoglycan Destruction of proteoglycans
unravelling collagen and other proteins

Cartilage breakdown
 Diagnosis
Clinical and laboratory Clinical
Knee pain plus at least Knee pain plus at least
five of nine: three of six:
Age >50 years Age >50 years
Stiffness <30 minutes Stiffness <30 minutes
Crepitus Crepitus
Bony tenderness Bony tenderness
Bony enlargement Bony enlargement
No palpable warmth No palpable warmth
ESR <40 mm/hour 95% sensitive
RF <1 : 40 69% specific
SF OA
92% sensitive
75% specific
Primer on the Rheumatic Diseases 13th ed. Springer, New York. 2008; 669-682.
 Diagnosis
Clinical and radiographic
Knee pain plus at least
one of three:
Age >50 years
Stiffness <30 minutes
Crepitus
+
Osteophytes
91% sensitive
86% specific

Primer on the Rheumatic Diseases 13th ed. Springer, New York. 2008; 669-682.
 Generalized OA
Heberdens nodes
Bouchards nodes
 OA Management
Cannot be cured
Treatment directed at symptoms and
slowing of progress of conditions
 OA Management
Management objectives:
Control pain adequately
Improve function
Reduce disability
The three types of evidence to consider for
evidence based management

Expert
Research opinion

Patient
opinion
 ACR 2000 Guidlines-
Drug Therapy Options in Osteoarthritis

Baseline program
(Weight loss/exercise)

Mild/moderate Moderate/severe
Pain pain/inflammation

Acetaminophen Steroids COX-2 specific

Inhibitors

OTC NSAIDs HYALURONAN Traditional NSAIDs

Tramadol (plus gastroprotection)
Propoxyphene
Opioids
Surgery
Hunter DJ. Ther Adv Musculoskel Dis 2009; 1: 35-47
Felson DT. N Engl J Med 2006; 354: 841-848
 Acupuncture
This is an ancient treatment
Mecanisms of action including release of
endogenous opioid
Some meta-analyses do report pain relief
compared to placebo
Felson DT. N Engl J Med 2006; 354: 841-848
 Acetaminophen (parasetamol)
Efficacy
Safety 1 g up to 3-4 times daily
Low cost
Ready
 Oral NSAIDs/
selective COX-2 inhibitors
Unresponsive to safer analgesic
COX-2 selective to be as effective as NSAIDs
NSAIDs can cause serious GI complications
COX-2 selective are less toxic to the GI tract
than NSAIDs combined with a PPI
Cardiovasular risk was increased with
rofecoxib, diclofenac, indomethacin, and
probably meloxicam
 Oral NSAIDs/
selective COX-2 inhibitors
Celecoxib increased risk at doses higher than
200 mg/day
Direct renal toxicity
NSAIDs are effective for symtom relief in OA,
and should be prescribed at the lowest
effective dose for the shortest possible
duration
 Intra-articular steroid
Block action of phospholipase A2 which
prevents conversion of phospholipid to
arachadonid acid
Inhibit vasodilation thereby decreasing edema
and pain
Ideally should be given at most every three
months
 Amitriptyline and antidepressants
Low dose amitriptyline may be considered for
refractory pain in patients who also have non-
restorative sleep
Depression is a common comorbidity and
succesful treatment of their depression can
improve pain and disability
 Opioids
Weak opioids Stronger opioids
Codein Oxymorphone
Dyhidro-codein Oxycodone
Tramadol Fentanyl
Morphine sulfate
 Side effects
Nausea
Constipation
Opioids

Dizziness
Confusion
Somnolence
Itching
Urinary retention
Respiratory & central nervous system depression
 Disease Modifying Osteoarthritis Drugs
(DMOADs)
Glucosamine sulphate
Chondroitin sulphate
Doxycycline
Diacerein
Risedronate
Hyaluronic acid (HA)
Avocado/soybean unsaponifiables
Strontium ranelate
Anandacoomarasamy A, March L. Ther Adv Musculoskel Dis 2010; 2: 17-28
Hunter DJ. Ther Adv Musculoskel Dis 2009; 1: 35-47
Glucosamine sulphate
May stimulate
proteoglycan synthesis
Mild anti-inflammatory
properties
Chondroitin sulphate
Stimulates RNA
synthesis by
chondrocytes
partially inhibits
leukocyte elastase
overcomes dietary
deficiency of sulphur-
containing amino acids
 Doxycycline

Inhibits matrix
metalloproteases
 Diacerein

Inhibits IL-1 synthesis

and activity
Effect of diacerein/rhein on the IL-1 system

Marthel-Pelletier J, Pelletier JP. Ther Adv Musculoskel Dis 2010; 0: 1-10

 Hyaluronic acid

Bone

Cartilage
HA
Capsule
Chondrocytes
HA

Synovial
Osteoblast Osteoclast
lining

Bone

Synthesis: Synoviocyte, chondrocyte

Hyaluronan works on cells that was involved in joint destruction

Hyaluronan

Inflammatory cells synoviocytes Chondrocytes

Decreases cells activity viscoinduction Improves cells metabolism

Neosynthesis of endogenous HA

JOINT CARTILAGE
Decreased inflammatory Reconstruction on Matrix synthesis
process supervicial level

Improves tissue integration

Pharmacologic activities of HA
Avocado/soybean unsaponifiables
Repress chondrocyte
catabolic activities
Inhibit inflammatory
mediators
Strontium ranelate
Stimulate the synthesis
of type II collagen and
proteoglycan
 New targets under evaluation
Calcitonin
Vitamin D
Cathepsin K
ADAMTS5
Prostaglandin E2
iNOS
Histamin
Nerve growth factor (NGF)
Anandacoomarasamy A, March L. Ther Adv Musculoskel Dis 2010; 2: 17-28
Thank you