New Biologic Therapies for Joint Disease

Take Home Message: Newer biologically based therapies involve two complementary approaches: 1) inhibiting cartilage breakdown (catabolism) and 2) enhancing cartilage synthesis (anabolism). Currently used therapies include autologous xonditionedserum(ACS), which provides therapeutic effect by inhibiting interleukin-1 (IL-1) as well as increasing the anabolic growth factor concentrations. Its effectiveness as an intraarticular therapy has been defined. Pl atelet rich plasma (PRP) has bee n used intraarticularly but still requires further evidence for proof of efficacy.

I. INTRODUCTION

Improved understanding of critical mediators in equine traumatic arthritis and osteoarthritis (OA) has led to the identification of multiple possible targets for therapy.¹ Biologically based therapies can be grouped into two complementary approaches:

1. Inhibiting cartilage breakdown (catabolism).
2. Enhancing cartilage synthesis (anabolism) (Fig. 1).²

Although there are multiple possible targets for inhibiting catabolism, most attention has been paid to IL-1 as well as metalloproteinases and aggrecanase.

This paper reviews the current use of the autologous conditioned serum products,^1,2 and PRP in treating joint and other soft tissue injuries and disease in the horse.

II. AUTOLOGOUS CONDITIONED SERUM^A,B

It has been demonstrated using intra-articular gene therapy with interleukin-1 receptor antagonist (IL-1ra) and an adenoviral vector that OA can be prevented proving the importance of IL-1 in the equine OA cascade (Fig. 2).^3,4 Specific anticytokine therapy in general has been a new approach for treating diseases such as rheumatoid arthritis, but because of problems with reactivity to the adenoviral vector, gene therapy is still not a reality. There is no specific IL-1ra serum and initially having the trade name Orthokine^® has a significant increase in IL-1ra as one effect of the process.^5,6 The principle is that the patient’s blood is incubated in a container with coated beads for 24 hours, centrifuged and then the resulting “conditioned” serum injected intra-articularly.
 

Orthokine was tested in horses in Europe initially by Dr Thomas Weinbergerc and he found that it was particularly beneficial in OA of the distal interphalangeal joint not responding to triamcinolone and hyaluronan (HA). Work with human blood examining the IRAP and IRAP II systems shows increased IL-1ra as well as IGF-1 and TGF-β but also increases in IL-1 and TNF-α.⁷ This product was evaluated using the Colorado State University (CSU) experimental
model of equine OA.⁸ In a 16-horse study with unilateral OA, eight horses received three injections of IRAP into the OA joint and the other eight horses received intra-articular saline at the same time. Treatment was initiated at two weeks and a total of three treatments administered at weekly intervals. Horses treated with ACS were observed to have significantly reduced lameness in OA limbs, even five weeks after the last treatment, compared with placebo-treated horses.⁸ There was also a significant reduction in synovial membrane inflammation in treated compared with placebo OA joints at day 70 and a trend for improvement in cartilage gross score and proteoglycan staining in ACS treated OA joints compared with placebo treated OA joints.

When Orthogen discontinued Arthrex as its licensee in the United States, Arthrex developed IRAP II. Comparative cytokine profiles of IRAP and IRAP II using equine blood were then performed in the author’s laboratory and have been reported.⁷ Both products had significant increases in IL-1ra concentrations, but the IRAP II system was significantly superior to IRAP. Of more importance, it was noted that the IL-1ra:IL-1 ratio was significantly better with IRAP II. The production of the growth factors IGF-1 and TGF-β were both increased to about double the levels of serum with no difference between the products. It was also noted that IRAP produced significantly more TNFα than IRAP II and this was considered to be a significant issue because of the known deleterious effects of TNFα.

III. PRACTICAL USE OF IRAP IN THE TREATMENT OF EQUINE JOINT DISEASE

The author has limited his use of IRAP to joint disease because this is where we have demonstrated efficacy and generally recommends the use of PRP products in tendons and ligaments (however, there is evidence in humans for usefulness for PRP in OA as well). Based on our research findings, the following are recommended volumes for individual joints:

• Carpal, fetlock, distal interphalangeal joints and tendon sheaths – 6mL
• Stifles – 10-12mL

Based on a recent retrospective study of equine veterinarians in the United States,⁹ the use of intra-articular autologous conditioned serum (IRAP and IRAP II products) was greater with sport horse veterinarians compared with racehorse veterinarians. Some of this difference is attributable to costs but use is greater in racehorses outside the United States because of longer withdrawal times for intra-articular corticosteroids.

IV. PLATELET-RICH PLASMA

The term PRP has become a buzzword in the mainstream media – especially in the treatment of high-profile human athletes. Ultimately, veterinarians are responsible for interpreting the science, determining the appropriate indications and counseling patients about what PRP can and cannotaccomplish.

PRP has been advocated as a way to introduce increased concentrations of growth factors and other bioactive molecules to injured tissues in an attempt to optimize the local healing environment. It has been used extensively in dental and cosmetic surgery for almost 30 years. Recently, it has become increasingly utilized for a variety of orthopaedic (musculoskeletal) applications.^10,11 There have been various definitions of PRP, but the consensus now is that the product should have an increase in platelet content over the level in blood. The initial enthusiasm for PRP was based on growth factors within the α-granules including transforming growth factor-β (TGF-β), platelet-derived growth factor (PDGF), insulin-like growth factor-1 and -2 (IGF-1 and -2), fibroblast growth factor (FGF), epidermal growth factor (EGF) and endothelial cell growth factor. There are a number of other bioactive factors in PRP contained in dense granules of platelets¹⁰ and there is an emerging paradigm that more than just platelets are playing a role in PRP.¹²

The basic principle of PRP is the selective separation of anticoagulated whole blood (plasmapheresis) via centrifugation. There are differences in the commercial systems with single spin and double spin systems with consequently different levels of platelet concentration (as well as different levels of leukocyte concentration).¹¹

V. THE USE OF PRP TO TREAT JOINT DISEASE

The use of PRP to treat joint disease in the horse is increasing. At CSU’s Orthopaedic Research Center (ORC) we have tended to recommend IRAP and IRAP II for joints and PRP (or autologous conditioned plasma (ACP)) for treatment of tendon and ligamentous injuries. However, good clinical results with OA in humans have been reported, ¹³ and recent in vitro work in our laboratory has shown beneficial effects on cartilage metabolism.¹⁴ Also, when administered via intra-articular injection in ovine subjects, PRP increased cartilage healing¹⁵ as well as superior healing in a meniscal defect model.¹⁶ In a comparative study in human OA, PRP was superior to HA but randomized,¹³ controlled studies are needed. 

VI. PLATELET VERSUS WHITE CELL DEBATE

Initial studies of the bioactive molecules in PRP focused on growth factor concentrations that are related to platelet numbers. [...]