Researcher: Horses with osteoarthritis could one day benefit from a preventive approach using PAAG.
In a “new uses for old things” twist, an equine veterinarian in Qatar has reported that a 2.5% hydrogel originally designed as a cosmetic filler can help horses with early stage to chronic osteoarthritis (OA) and could even one day be used to help prevent joint damage.
Florent David, DVM, MS, Dipl. ACVS & ECVS, Dipl. ACVSMR, ECVDI Assoc., specialist in Surgery, Sports Medicine & Rehabilitation, and Diagnostic Imaging at the Equine Veterinary Medical Center, in Doha, described what he found in published research on the product at the 2019 Northeast Association of Equine Practitioners Symposium, held Sept. 25-27 in Saratoga Springs, New York.
David began by explaining that there are two polyacrylamide gels designed for horses—Noltrex Vet (4%) and Arthramid Vet (2.5%). He said he has been involved with clinical research on both and hasn’t received renumeration or benefits from either company. More recently he’s conducted research on Arthramid Vet, which he focused on primarily in the current research review.
At the time of this presentation, scientists had not compared the two drugs directly but had completed and published individual research studies in peer-reviewed journals.
Doctors use a variety of hydrogels for cosmetology, and “they’re actually very different,” David said. “Polyacrylamide hydrogels are not all the same, and we should be aware of that.”
He said researchers in Denmark have reported the 2.5% gel is nontoxic, biocompatible, and stable with great tissue integration in joints from various species, including horses. “It’s a gel, produced by a patented technology, that’s basically made of a 3D network of cross-linked polyacrylamide polymers. During the manufacturing process water molecules are forced between the polyacrylamide chains, generating a porous biomaterial with great molecular stability and ability to maintain its viscoelastic properties in situ. The lightly bound water molecules in the gel can easily interchange with water from the surrounding tissue.”
The product is approved for use in New Zealand, he explained, and it’s awaiting approval for use in many other countries. David said scientists speculate that the gel works by improving the joint capsule elasticity lost during the osteoarthritic process. The gel might also protect the joint surfaces from exposure to cytokines, which are inflammatory molecules the immune system produces.
“The facts are little, I would say,” he added. “We know that the gel is integrated (into the joint), produces synovial hyperplasia, and this appears to give the joint a stabilizing effect on the joint capsule and synovium (lining) with a subsequent increase in elasticity and tensile strength. There may be more undiscovered effects, as well.”
David acknowledged that most of the 2.5% PAAG clinical studies have been uncontrolled, usually in cases that didn’t respond to typical intra-articular (IA) joint injections. Here are the studies he reviewed:
- In 2012 Janssen et al. used 2.5% PAAG to treat 12 horses that had been lame for three or more months due to coffin joint OA. The veterinarians had diagnosed the horses using clinical signs, IA anesthesia (joint blocking), radiographs (X rays), and MRI, and all horses had been treated previously with triamcinolone acetonide and sodium hyaluronan, and/or autologous conditioned serum. The scientists injected the horses’ coffin joints with 1 milliliter of the 2.5% PAAG. They saw no side effects in any of the horses. Six months after the injections, eight horses (67%) were lameness-free, two were improved, and two hadn’t responded to treatment.
- In 2014 Tnibar et al. conducted a controlled trial on the efficacy of 2.5% PAAG in fetlock joint OA. Forty sport horses were enrolled in the study—20 in each group. Veterinarians diagnosed OA using IA anesthesia, radiographs, and MRI and treated one group with 2 milliliters 2.5% PAAG and the other with 10 milligrams triamcinolone acetonide plus 20 milligrams sodium hyaluronate (TA-HA). Clinicians blinded to the treatment assessed lameness at one, three, and six months post-injection. “It outperformed triamcinolone at every time point,” said David, with 55% of horses in the PAAG group sound versus 15% in the TA-HA group at one month; 65% vs 40% at three months; and 75% vs. 35% at six months.
- In 2015 Tnibar et al. studied 43 horses (65% sport horses, 19% racing, 16% others) with single-joint OA: 63% of the joints were in the forelimb, 93% were fetlocks, and 86% had undergone previous OA treatment. Clinicians performed a blinded assessment of lameness. At one, three, six, 12, and 24 months after injection with 2 milliliters 2.5% PAAG, 59%, 69%, 79%, 81%, and 82.5% of horses were lameness-free, respectively. He added that 78% of the horses had no joint effusion (fluid swelling) at the final time point.
- Bathe et al. performed a prospective study in 20 sport horses with proximal/distal interphalangeal joint (pastern or coffin joint) OA-associated lameness in 2016. Veterinarians diagnosed all horses on MRI, and all horses were persistently lame after previous corticosteroid treatment for an average of 15-plus months. Horses were 3/10 lame on Day 0 and received IA injections of 1 milliliter 2.5% PAAG. Of 18 horses available for follow-up a median of 12 months later, 12 had returned to full function, three to a lower level, and three failed to improve.
- In 2019 Clifford et al. (David’s research team) performed a pilot study in 89 painful joints in 49 flat-racing Thoroughbreds. Of those joints, 88% were mid-carpal (knee) and 12% fetlock, and none had received IA medication in the two months prior to the study. Lameness grades prior to injection were mainly 2/5 and 3/5 lame, with radiological scores of 0/3 and 1/3 in most cases; this indicated “no-to-mild OA changes on the radiographs,” said David. The clinician assessing lameness was blinded to what treatment the horses received; veterinarians injected 2 milliliters of 2.5% PAAG IA. There were no side effects or adverse reactions in any of the treated joints, and the percentage of lameness-free horses included:
- 0% at one week;
- 43% (21/49) at four weeks;
- 3% (33/49) at 12 weeks; and
- 3% (32/49) at 24 weeks (one horse regressed).
He explained that a further 14.3% (7/49) improved enough to remain in race training. “The largest reduction in lameness scores occurred at four weeks, with some taking up to 12 weeks after treatment to respond, and no further improvement in lameness between 12 and 24 weeks was observed,” he said.
“We came back with a single-site double-blinded prospective study on the comparative efficacy of 2.5% PAAG with intercarpal joint lameness,” he said.
They performed the study in 33 flat-racing Thoroughbreds with confirmed intercarpal (knee) joint pain based on clinical findings that included lameness, joint effusion, and reaction to flexion, along with IA anesthesia and radiographic assessment.
The team studied three treatment groups: The first received 2 milliliters 2.5% PAAG, the second 10 milligrams triamcinolone acetonide, and the third, 20 milligrams sodium hyaluronan IA, followed by two 40 milligrams intravenous (IV) injections at weekly intervals. The horses rested for 48 hours after the injection and resumed an unaltered training regimen. Clinicians examined the horses at two, four, and six weeks and continued to examine the 2.5% PAAG group through to 12 weeks. They based treatment success on whether the horse was sound.
“It definitively outperformed the other treatments, even in the early phase of joint pain/OA,” he said. “We looked at them at 12 weeks, (and) the horses that were lame-free at six weeks were still lame-free at 12 weeks with the 2.5% PAAG.”
Finally, David reviewed one uncontrolled, unblinded study on 4% PAAG, in which McClure and Wang (2017) noted a significant decrease in lameness score in 23 of 28 (82%) treated horses at Day 45 after treatment and 21 of 28 (75%) horses at Day 90, compared to baseline. He said there was “regrettably no data on the number of lameness-free horses in this study.”
“If you can improve your quality of life, that’s a different story,” he said. “If we are to look at something with those products, better to look at the lame-free, because this is what our industry is a lot about.”
Expectations and Moving Forward
David said veterinarians initially used PAAG for chronic OA cases, but he’s beginning to think it’s better to apply it earlier as a first-intention therapy.
“Some people are even talking prophylactic (preventive) use,” he said, “but we’re far from having data to support this.”
Here are some things he said veterinarians and researchers need to consider as they move forward in understanding and using PAAG:
- Before treating a joint, it’s important to “prove the painful joint is really the painful joint.” Don’t pursue treatment unless you’re sure.
- “(The PAAGs) are not miracle products, we need to be realistic of what to expect of them. Intra-articular fractures or osteochondral chips should still be treated surgically (fracture repair and arthroscopic chip removal) when indicated, and PAAGs are not made to replace surgery.” he said.
- “There is anecdotal evidence suggesting PAAGs could be taking a share in the successful management of subchondral bone cysts, but proper data are lacking currently.”
- “We should not wait to fire the PAAG bullet until we have obvious evidence of OA on the radiographs (before deciding to treat),” he said. “There is now evidence that early in the disease process PAAGs perform better than corticosteroids or hyaluronic acid.”
- David broached whether veterinarians can combine the drug with other medications, noting that they might one day consider administering it along with bisphosphonates. “It’s better to give the drug on its own, but let’s say the horse is not responding,” he said, adding that there’s “no proof … at the moment.”
- Veterinarians and horse owners need to keep in mind the delayed response to PAAG treatment—David says this delay is normal, but it’s not what clients are accustomed to with joint treatment. “PAAGs take three to four weeks, and sometimes up to six weeks, to take effect,” he said. “They are not anti-inflammatory drugs or painkillers and, as a result, it requires a different mindset of the trainer and owner expectations, compared to traditional therapies.”
He said the main and most important question today is how much to inject in each joint, a question he answered with a list of suggested doses (see sidebar). Post-injection protocols range from horses resting for 24 to 48 hours only before returning to training to four weeks of exercise restriction (swimming, water treadmill, hand/saddle walking) before return to proper exercise.
“There’s evidence to suggest a dose-dependent response,” he said. In other words, the smaller the dose, the less the response.
“Reassess the horses between three and six weeks. A second dose should be considered for ‘partial responders,’ especially if a low volume was injected first,” he said, noting that repeat doses can be given at six to 12 months, only if needed.
Overall, David is encouraged about the possibilities 2.5% PAAG presents veterinarians and lame horses.
“There is mounting evidence that these new products are a game changer in the management of joint pain in osteoarthritis, and I’m very glad we have those products available,” he said. “A lot of everything has been tried on the horses I usually see. I’m very happy to have this medication available, despite the high price. I’ve been able to return a large number of athletes of all kinds, struggling with their careers, to the sport.
“Based on their mechanism of action and their relatively slow integration in the synovial membrane to obtain benefits on the joint capsule elasticity and joint pain, PAAGs are not products that are under the radar from a doping point of view as painkillers and corticosteroids would be.
“It is a very, very safe product,” he added. “I’ve never had to go and flush a joint after hundreds of joints injected up to now. I sometimes get a mild flare, as you can get with any IA medication, but this is about it. In my hands, Arthramid Vet has been a very safe product to use.”