Degenerative Joint Disease Intraarticular Therapy Update and Review
Victoria R. Maxwell, DVM
Intraarticular therapy remains an effective and useful tool in addressing joint related lameness
issues in the equine patient
FDA approved
Corticosteroids
Hyaluronan
Hyvisc & Hylartin V
Hyalovet & Legend (IA & IV)
PSGAG
Adequan
Non FDA drug approved
Pentosan Polysulfate &Map 5
Polyglycan & Chondroprotect
1. Equiine Lameness
Rigors of “use trauma” allow the forces of destruction to outweigh normal repair 1(Mackay-Smith,
Baker, Rooney)
Lectures Objectives:
Focus on pathophysiology of DJD
Cytokines and their role in inflammation
IA Therapeutic Options
2. Anatomy & Physiology of Joints
Joint Components
External Support Structures
Joint Capsule
Synovial Membrane
Hyaluronan
Articular Cartilage
Subchondral Bone
Articular Cartilage
Proteoglycan Complex
Articular Cartilage
Proteoglycan complex
Glycosaminoglycans (GAG’s)
repeating disaccharide units
The most important GAG’s in joints
Hyaluronic acid; non sulfated
Chondrotin Sulfate 4 & 6
Keratin Sulfate
Articular Cartilage
Chondrocytes are small in number, only “living” element that make up articular cartilage
Maintain homeostasis
Very
metabolically active
Low mitotic rate 3 (Rooney)

No vascular, nerves or lymphatics in adult articular cartilage
3. Disease Process
Synovial Membrane Reaction to Injury
Articular Cartilage Response to Injury
Response of Subchondral Bone to Injury
Clinical Interpertation
Arthritis Pathophysiology
Direct mechanical damage of matrix (Thiabault et al. 2002)
Reduction in joint width space
Articular cartilage atrophy
Chondrocyte death
Superficial cells more vulnerable (Chen et al 2003)
Irreversible changes due to mediators 4 (Riggs)
4. Mediators
Inflammation
Compared with normal cartilage, osteoarthritis-affected cartilage is insulted with inflammatory
mediators McIlwraith 1996
Matrix Metalloproteinase (MMP)
Interleukin (IL)-1 α & beta
Prostaglandin (PG) E2
Tumor Necrosis Factor (TNF)-

Nitric Oxide-NO 6 McIlwraith)
Inflammatory Mediators
Soluble molecules of mainly peptides and proteins that mediate cell to cell communication and
show their physiological effect over
Short distances
Short time spans
Very low concentrations nano- to picomolar concentrations 12 (Spiers)
Cytokines in Cartilage Homeostasis
Anabolism-synthesis
IGF-1
FGF-2
TGF-beta
VEG
BMPs
TNF α
Cytokines
Cytokine Receptor Interaction
Pro-inflammatory Cytokines
Interleukin 1
IL-1 α- IL-1 Beta
IL-1ra
Proposed IL-1 beta most important catabolic enzyme in OA (Carmona 2009)
However a knockout mouse without Il-1 gene still showed accelerated OA.
Inhibits both proteoglycan and type-II collagen synthesis
Promotes
cartilage degradation and activates collagenase and stromelysin
bone resorption by activating osteoclasts through intermediary cytokine
Recent work by Little et al suggest IL plays a regulatory role and it’s role in OA initiation may not
be as critical as previous thought. 9 (Carmona 2009)
Stimulates
Interleukin RA
IL-1RA antagonist (human recombinant) has been shown to reduce progression of
experimentally induced DJD in humans
(Anakinra-Kineret received daily sub Q injections results seen at 24 weeks)
Administration of proteins is a major weakness for a drug delivery system, look to gene therapy
here 8 (Pelletier 2001)
IL-1 receptor antagonist with Adeno virus (Dr. Frisbie and Dr. Nixon)
Transient effect 28 days with synovial inflammation10 (Frisbee)

Matrix Metalloproteinase
Area of intense research
MMP
Normal development and turnover
Elevated activity in pathologic conditions
Tissue inhibitor of metalloproteinase-TIMP 1-2-3-4
Specific inhibitor, 1:1 abolishes MMP activity (Sleter et al)
Imbalance
between MMP and TIPM initiates cartilage matrix digestion
transitioning anabolic state to a catabolic state

While stromeolysin (MMP3) was considered the main agent responsible, more recently it appears
that aggrecanase causes most of the proteoglycan degradation in OA11
Matrix Metalloproteinase- MMP
Many enzymes that degrade ECM are upregulated by IL-1 beta and TNF alpha
Matrix
MMP's may be subdivided into joint inflammation (McIlwraith 1996) (Pelletier,
Pelletier,2001)
collagenase
gelatinase
stromelysin (McIlwraith 1996)
MMP 1,8,13
Collagenase 1,2,3
MMP 2,9
Gelatinase A,B
MMP 3,10,11
Stromelysin 1,2
Aggrecanase
MMP 1 (synoviocytes) & MMP 13 (chondrocytes) prominent roles in OA
5. Therapeutic Choices
Accepted Therapy
Three main pharmaceuticals currently used in joint (intra-articular) injections—
Sodium hyaluronate (HA)
Polysulfated glycosaminoglycans (PSGAG)
Corticosteroids
Hyaluronan
Most widely used IA medication in equines
Produced naturally by membrane bound enzyme HA synthase
Compression
strength to AC as the core molecule for proteoglycan complex
Viscoelastic nature to synovial fluid 7 (Caron)

HA
It is known that the half-life of intra-articular HA injected into normal equine joints is around
hours- reduced in diseased joints
Most of this HA is rapidly cleared from the joint, some remains associated with the synovial
membrane and provides benefits in the intercellular spaces of the synovial membrane
HA has direct anti-inflammatory effects in inhibiting inflammatory cells 13 (Kawcak)
HA
Direct anti-inflammatory effects by inhibiting inflammatory cells.
May also reduce interactions of enzymes or cytokines through the steric hindrance project.
* It is most recently felt that the decreased inflammatory cell
activity is through interaction of
HA with cell receptors
on the white blood cells. 13
Corticosteroids
Extremely effective at eliminating inflammation from within the joint.
hydrostatic pressure decreases within the joint decreases
 joint capsule decompresses, and the discomfort (pain) is eliminated.
Potential side effects
*studies indicate judicious use of intraarticular steroids does more good than harm
14
(Trotter)

Corticosteroids
Steroids promote the degradation of hyaluronan:
thin synovial fluid consistency
loss of protection of the articular cartilage layer
accelerated joint degeneration
Since steroids also have a deleterious effect to the joint environment not uncommon to use in
conjunction with HA or PSGAG
Corticosteroids
Methylprednisolone acetate (Depo-Medrol) --Longest-lasting of the three; typically used in
low-motion joints for degenerative joint disease.
Colorado State University (CSU) research has shown that this drug does have negative effects on
articular cartilage


Triamcinolone acetate (Vetalog)--Moderate duration of effectiveness; used in high-motion
joints at low dosages.
CSU showed no negative effects and an increase in the synthesis of essential articular cartilage
elements (chondroprotective)
Betamethasone phosphate (Betavet Soluspan, Celestone)--Shortest-acting of the three;
used to reduce synovitis and joint inflammation;
Adequan IA: History
In 1981 FDA approval of Adequan (PSGAG) as an intra-articular treatment for equine DJD was in
U.S.
Basis for development
Successful human use of IA PSGAG
Successful reports of efficacy in horses in German veterinary literature
Successful use at U.S. Standard bred tracks
Adequan
There have been numerous studies of PSGAG.

PSGAG
has been shown to inhibit the effects of various enzymes associated with cartilage
degeneration, including both collagenase and stromelysin, serine proteinases and others 16
(Caron)
PSGAG also has been shown to have a direct inhibitory effect on PGE2 synthesis and it is
suggested that there is an anti-IL-1 effect
PSGAG also stimulates the synthesis of hyaluronic acid in the horse
The recommended dose of Adequan in horses is 250mg once a week for up to five weeks, intraarticularly
Inhibition of Catabolic Enzymes by Adequan
Stromelysin (neutral metalloproteases) very potent degrader of PG complexes
May, S, Hooke R, Lees P, The Effect of drugs in the treatment of OA on Stromelysin
(proteoglycansase) of equine synovial cell origin. Brit J Pharmacol 93 281
Elastase degrades a wide range of connective tissues including collagen and proteoglycans
Baici A, SalgramP, Fehr K, Boni A: Inhibition of human elastase frompolymorphonuclear
leukocytes by a glycosaminoglycan polysulfate (Atreparon). Biochem Pharmacol 29 1723-1727
1980
Hyaluronidases degrade HA
Greiling H: Biochemical investigations of the mode of action of Arteparon. IX Europ Cong
Rheumatol Eular Basil 1980 pp11-18
Diminish matrix molecule breakdown
Todhunter, R.J. and Lust G. Polysulfated glycosaminoglycans in the treatment of osteoarthritis.
J.Am. Vet. Med. Assoc 4-15 1994; 204 (8) 1245-51

Adequan IA Dose Response Conclusions
A dose of 250 mg PSGAG given by intra-articular injection once weekly for 4 weeks led to
significant improvement in
 lameness
carpal swelling
carpal flexion
synovial fluid protein
stride length.
A higher dose (500 mg) was not significantly more effective IA.
20 Adequan, Luitpold Pharma, Inc.
6. Adequan Recent Research
Evaluation of Intraarticular Polysulfated Glycosaminoglycan or Sodium Hyaluronan for Treatment of
Osteoarthritis Using an Equine Experimental Model
David D. Frisbie, DVM, PhD, DACVS; Chris E. Kawcak, DVM, PhD, DACVS; Natasha M. Werpy,
DVM; C. Wayne McIlwraith, BVSc, PhD, DACVS
Study Objective
To asses the clinical, biochemical and histological effects of intraarticular polysulfated
glycosaminoglycan (PSGAG) or sodium hyaluronan (HA) in the treatment of experimentally
induced osteoarthritis (OA) in horses.
OA induced by arthroscopy in one middle carpal joint of each horse
N=24 horses
8 PSGAG
8 HA
8 control
Materials and Methods
This was a double blinded experimentally controlled randomized block design utilizing 24 horses
in an established model of osteoarthritis (OA).
Osteoarthritis was induced in one carpal joint of each horse. On days 14, 21 & 28 horses
received one of 3 intraarticular treatments:
1) 250 mg PSGAG + 125 mg amikacin
2) 22 mg sodium hyaluronan + 125 mg amikacin and
3) 2ml 0.9% NaCl + 125mg Amikacin (PCB)
No adverse treatment-related events were detected.
Results
Histological- synovial membrane vascularity and subintimal fibrosis was significantly reduced with
PSGAG compared to PCB.
Significantly
less fibrillation was seen with HA treatment and a similar trend was seen with
PSGAG when compared to PCB.
Biochemically
improved glycosaminoglycan synthesis was seen with PSGAG when compared to
HA or PCB.
Results
Although the model induced a significant change in clinical parameters, no significant treatment
effects were demonstrated, with the exception of improvement in synovial fluid effusion with
PSGAG when compared to PCB.
Histologically the degree of synovial membrane vascularity and subintimal fibrosis were
significantly reduced with PSAG treatment compared to PCB.
A trend for similar results was seen in synovial membrane from HA treated horses.
Histologically significantly less fibrillation was seen with HA treatment and a similar trend with
PSGAG when compared to PCB.
Take Home Message
The use of intraarticular polysulfated glycosaminoglycan or sodium hyaluronan showed disease
modifying effects and performed significantly better than placebo treatment in experimental OA.
The results of this study support use of both these products of equine osteoarthritis.
BEVA 2005
Retrospective study of distal interphalangeal joint (DIP) to assess the efficacy of PSGAG Adequan
and Methylprednisolone acetate (MP)
Successful outcome for 76% of patients receiving Adequan exclusively
Success was 46 % of patients that received MP prior to Adequan therapy (due to ineffective MP
response)
Treatment with MP prior to PSGAG therapy is associated with a poorer prognosis than use of
PSGAG alone.
7. Adequan Safety
Adequan IA Safety Issues: A History
When Adequan IA was introduced a higher than expected number of adverse reactions were
reported from the field
Why did these unexpected reactions occur?
Prior to Adequan IA, only corticosteroids were used for IA injection (containing antimicrobial
preservatives)
Good aseptic injection technique was not perfected
Adequan IA was unpreserved and packaged in snap-top glass ampoules.
Adequan IA Safety Studies at CSU
preliminary studies, CSU established a maximum dose of Staphylococcus aureus bacteria that
could be injected into a joint without causing sepsis
33 colony forming units
sub infective dose
In
CSU Safety Studies
4 groups of 8 horses had injections of this sub infective dose of Staph bacteria into the carpal
joint
The results for each group:
Saline group: 0/8 joint infections
DepoMedrol group: 3/8 joint infections
Hylartin-V group: 5/8 joint infections
Adequan IA: 8/8 joint infections
CSU Safety Study # 2
Prevention
3 groups of 8 horses given the sub-infective dose of Staph bacteria with:
250 mg Adequan IA
250 mg Adequan IA drawn from the ampoule w/filtered needle
250 mg Adequan IA with 125 mg amikacin
Results
8/8 joints infected in the Adequan IA group and in the Adequan IA group with filtered needle
0/8 joints infected in the Adequan IA + 125 amikacin group
CSU Safety Studies
It was concluded that:
Effect of Adequan IA on potentiation of a sub-infective dose of Staph bacteria confirmed
 The potentiation of infection was completely prevented by adding 125 mg amikacin to injection
Amikacin did not react in with PSGAG
*
CSU data that says 125 mg (0.5 mL) amikacin is effective at preventing joint infections
IA Therapy Conclusion
Cartilage integrity is a balance between cytokine driven anabolic and catabolic processes
Excess pro-inflammatory cytokines drives the OA process
Adequan is the only pharmaceutical therapy to address anabolic and catabolic effects of OA
Therapeutic targets are concentrating on prevention and disease reversing therapies
Despite explosive growth the understanding of how individual inflammatory mediators are
regulated story remains incomplete
Rely on evidence based medicine as the future evolves
OA Conclusion
It is impossible to prevent joint stress however the strive to minimize inflamed joint quickly before
permanent damage occurs is universal
One of keys to successful management and prevention of ongoing damage is early detection and
aggressive treatment
*
Strong medical science drives the medical/veterinary industry: the industry should not drive
veterinarian medicine
References available on request