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
Stimulates 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)
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;
AdequanIA: 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, intra-articularly
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
AdequanIA 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
AdequanIA Safety Issues: A History
When AdequanIA was introduced a higher than expected number of adverse reactions were reported from the field
Why did these unexpected reactions occur?
Prior to AdequanIA, only corticosteroids were used for IA injection (containing antimicrobial preservatives)
Good aseptic injection technique was not perfected
AdequanIA was unpreserved and packaged in snap-top glass ampoules.
AdequanIA Safety Studies at CSU
In 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
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
AdequanIA: 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 AdequanIA
250 mg AdequanIA drawn from the ampoule w/filtered needle
250 mg AdequanIA 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 AdequanIA 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