New treatments for osteoarthritis are always welcomed, and many times a cutting-edge product is presented at AAEP to advise practitioners of the possibilities to manage the equine athlete. It is thought that up to 60% of all lameness is attributable to osteoarthritis. One topic of discussion at the 2019 AAEP Convention focused on intra-articular administration of 2.5% polyacrylamide (PAAG) hydrogel (Arthramid).
The hydrogel used consisted of 2.5% cross-linked polyacrylamide and 97.5% non-pyrogenic water. The material is hydrophilic, homogenous, biocompatible and viscoelastic. It maintains its volume through continual exchange of water with the surrounding tissues. Following injection, cells are able to integrate into the synovium through blood vessel ingrowth, collagen deposition and water exchange. The hydrogel does not become encapsulated, but rather integrates within the tissues to stabilize the joint capsule and synovium while also increasing joint capsule elasticity to achieve improvements superior even to a normal joint.
One study by Leigh de Clifford, BVSc, Cert AVP, PGDipVPS, MVSc, et al. (Journal of Equine Veterinary Science, June 2019, vol 77; pp. 57-62) reviewed use of the hydrogel in a pilot study of 49 flat-racing Thoroughbreds. Lameness was improved at weeks 1, 4, 12 and 24.
A follow-up study evaluated results of use of this product in 33 flat-racing Thoroughbreds with lameness of Grade 1, 2 or 3 (on the AAEP scale of 0-5) that were in full training. Using radiology and intra-articular anesthesia, lameness pain was localized to the intercarpal joint. No horse was enrolled in the study if it had experienced a previous joint infection, arthroscopy within the preceding 12 weeks, or had intra-articular medications within the preceding four weeks. No horses with Grade 4 or 5 lameness were included in the study.
The double-blinded, randomized, prospective study evaluated treatment of the intercarpal joint with one of three medications: a) 2 ml of 2.5% PAAG; b) 12 mg triamcinolone; or c) 20 mg hyaluronic acid followed by two intravenous weekly doses of 40 mg HA. Following intra-articular treatment with any medication, the horses were given 48 hours of rest, then were returned to full gallop training. Some PAAG-treated horses experienced mild effusion for 5-7 days post-treatment during integration of the hydrogel with the synovium. This effusion improved with rest.
All horses were checked by a “blinded” veterinarian at 2, 4 and 6 weeks, and at 12 weeks for the 2.5% PAAG-treated individuals. Although no differences were seen by week two, at weeks 4 and 6, significant differences were seen in the 2.5% PAAG group. Resolution of lameness was considered a successful outcome—success occurred in 83% for 2.5% PAAG-treated horses, and 22-40% in the TA- and HA-treated horses. There was no significant difference between variables such as age, different speeds, lameness grade, effusion, flexion or manipulation scores.
The 2.5% PAAG-treated horses that were free of lameness at week 6 remained so at 12 weeks. The 2.5% PAAG-treated horses demonstrated superior results in lameness resolution, lessened joint effusion, and less reaction to flexion compared to the TA and HA groups. It should be noted that intra-articular administration of 2.5% PAAG takes 4-6 weeks following treatment to take effect and to elicit improvements in lameness scores.
Following the AAEP presentation, in conversation with tissue engineer Greg McGarrell, BSc, MBA, CEO of Nupsala Veterinary Services, he described two possible mechanisms of actions of PAAG. The first is its role as a scaffold that is incorporated into the synovial lining to substitute for missing/degraded tissue that is infiltrated with synovial fluid. In cases of chronic synovitis, synovial fluid within the degraded synovial membrane recesses inhibits tissue growth and interferes with disease modification. Injected hydrogel lays across the synovial membrane, which is only a 4-cell-thick intimal layer. There, the hydrogel is adsorbed as a scaffold that enables intimal cells and fibroblasts to proliferate and differentiate to thicken the membrane and produce normal synovial fluid within the joint that can then counteract inflammatory mediators such as cytokines.
Another mechanism of PAAG hydrogel is currently being investigated. McGarrell explained that joint capsule fibrosis in advanced osteoarthritis restricts movement, which wreaks havoc with footfall. Subsequent proprioceptive deficits cause distal limb pain nociceptors to fire constantly. This means that healthy, non-fibrotic joint capsule tissue has to work harder to move the limb, and that stimulates pain from joint nociceptors. In studies measuring elastin modulus following injection of Arthramid, increases in flexion of the diseased joint help dampen nociceptor firing that amplified pain.
He also described studies in dogs with severe elbow dysplasia—these dogs achieved 16% improvement in joint flexion following PAAG injection. Rather than osteoarthritis pathology being related to bone-on-bone, it might actually be a consequence of a fibrotic joint capsule and relief can come from improved flexibility. McGarrell advised that horses with improved joint flexion following PAAG injection respond more quickly and for longer to this disease-modifying medication.
To achieve the best results from PAAG hydrogel treatment, McGarrell advised that it is important to first resolve inflammation with triamcinolone or IRAP injection or even just to remove excess joint fluid, then follow two weeks later with the PAAG hydrogel injection.
He noted that arthritic disease is still present in treated horses, and osteoarthritic changes are influenced by exercise-induced trauma. PAAG hydrogel has the potential to modify the disease process by diminishing nociceptor response. The average duration of action in sport horses might be 18-24 months before a repeat injection is required. To maximize beneficial effects, husbandry changes—such as shoeing, training surfaces, or other predispositions to exercise-induced trauma—should also be managed appropriately.