Intraarticular Therapy Review Equine Degenerative Joint ...



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;

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, 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

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

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

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

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