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How veterinarians should combine the use of 2.5% PAAG (Arthramid® Vet) and Corticosteroids (Triamcinolone Acetonide)

Introduction

Joint treatments in horses due to osteoarthritis traditionally include rest, controlled exercise, corrective shoeing, nutraceuticals (including glucosamine, epiitalis, hyaluronic acid, and PSGAG's), non-steroidal anti-inflammatory drugs (NSAID’s), and any combination of the above, along with intra-articular medications including with corticosteroids (with or without hyaluronic acid) or biotechnological substances such as stem cells, platelet rich plasma, or autologous conditioned serum (IRAP). 2.5% PAAG is the most recent addition to this list. 

A recent survey of equine practitioners(1) revealed that whilst up to 87.5% of practitioners use at least some non-steroidal intra-articular therapies (NSIAT’s) to treat joint disease, corticosteroids (+/- hyaluronic acid) remain the intra-articular therapeutic of choice. 

Although there were some limitations to this study, including that the use of NSIAT’s could no doubt be either higher or lower than the actual use among the practitioners surveyed, there were other findings worthy of note; that experienced practitioners with a higher lameness caseload and those that performed intra- articular injections in more than 10 horses/month were significantly more likely to use NSIAT’s; that 12 out of the 353 practitioners rated PAAG as their first choice treatment; that the most cited reason why practitioners did not use NSIAT’s was the economic limitations of the client; and that the availability of PAAG was problematic for practitioners in the USA compared to other parts of the world. 

NSIAT’s used by practitioners include platelet-rich plasma, autologous conditioned serum, autologous protein solution, cellular therapies, and polyacrylamide hydrogel (PAAG). 

The authors in the survey concluded that whilst practitioners frequently use NSAIT’s, choosing to treat acute joint pathology more than previously reported, practitioners still have questions about the efficacy of these products and ideal treatment protocols in horses. A better understanding of the disease-modifying effects of these products and investigations into best practices for how and when these products should be used was recommended.  With this in mind, we wanted to share our experiences and thoughts on how we believe practitioners should consider combining the use of 2.5% PAAG with corticosteroids (triamcinolone acetonide TA). 

History of Intraarticular Corticosteroids in Horses

The use of corticosteroids for musculoskeletal conditions in horses was first reported in 1955 and they remain an important tool in the equine practitioners armamentarium(2).  Employed principally for their potent anti-inflammatory and pain relief effects through (primarily) inhibition of IL-1, TNF-𝛼, and COX-2 expression, controlled studies have clarified that whilst methylprednisolone acetate has deleterious effects on articular cartilage that exceed any potential anti-inflammatory benefits, triamcinolone acetonide (TA) has favourable effects on clinical lameness and on synovial fluid, synovial membrane, and articular cartilage morphologic parameters(2).

The efficacy of TA has been examined in an osteochondral fragment model at Colorado State University (CSU) where six horses had 12mg TA administered twice, on days 14 and 28 post-surgery. This was shown to cause a clinically significant reduction in lameness; the average lameness grade at day 72 post-surgery was reported as 0.63 (AAEP scale) with three horses (50%) perceived to be lame-free, two still being grade 1 and one horse being grade 2. 

Results from a more recent study(3) with only a single intra-articular injection of 12mg TA showed only 3/11 (27.3%) of the treated joints were still lame-free at 42 days after treatment. Whilst it is difficult to directly compare an experimental fragment model of joint inflammation to a naturally occurring joint disease model where none of the horses have osteochondral fragments, it asks the question as to why, at least in our experience, do we see such a variation in response to intraarticular medications? 

Why do we see such variations in clinical responses? 

A logical reason is that the response to treatment is influenced by the nature and state of the diseased tissues at the time. The term arthritis describes inflammation of the joint and incorporates synovitis, capsulitis, sprain, intra-articular fractures, meniscal tears, and osteoarthritis (OA). Sub-chondral bone injury also plays a role. These pathological conditions are defined as ‘a group of overlapping distinct diseases which may have different aetiologies, but with similar biologic, morphologic, and clinical outcomes’.  

As equine practitioners we acknowledge that understanding the complexity of disease processes associated with joint pain remains a constant difficulty and, as with any disease process, an accurate diagnosis is essential. But oftentimes, due to varying economic considerations, adequate time and money are not always made available for the veterinarian to properly diagnose, treat, and evaluate a horses' response to treatment before the owner's expectation of racing or performance. Hence, we oftentimes rely on the ‘art’ of veterinary practice to achieve effective outcomes. 

The influence of rest on a response to treatment might also be considered important. In human medicine a substantially protracted response to treatment (an increase of nearly 70%) was reported to accompany a strict regimen of rest and gradual return to use with rheumatoid arthritis of the knee(2). This practice has been extrapolated to equine practice but where only 24 to 48 hours of rest is commonly suggested. The best explanation provided for this recommendation is that it helps reduce clearance rates and allows better penetration of the medication into the intraarticular tissues. It may also reduce the incidence of hemarthrosis, but none of these suggestions have been fully investigated in the horse. Interestingly in our study(3) that included treatment in the face of ongoing exercise, the response rate of just 27.3% in the TA treated group was significantly lower than that seen in the 2.5% PAAG treated group (83.3%). This may support that more prolonged periods of rest, at least following TA administration, might produce better outcomes. 

The duration of effect of intra-articular corticosteroids might also play a factor in their perceived efficacy. Exogenous corticosteroids have both acute and chronic effects because of their effects on gene expression so it is difficult to directly transpose pharmacokinetic data into biologic potency or activity(2). Measuring gene expression may provide the potential for better assessment of pharmacodynamic responses and objectively allow the development of methods to better identify those cases that may be most responsive to treatment. These methods might also make it possible to aid the development of treatments that target more specific areas in joint injury and disease. But none of these methods are available in a practical sense at this time. Therefore, the need to make treatment decisions based on a combination of knowledge of the drug and experience with clinical outcomes remains. 

Efficacy of TA vs 2.5% PAAG

A recently published prospective double-blinded positive control study(3) directly compared the efficacy of 2.5% polyacrylamide hydrogel (2.5% PAAG- Arthramid Vet) in the treatment of middle carpal joint lameness in racing Thoroughbreds against treatments of triamcinolone acetonide (TA) or sodium hyaluronate (HA).

A total of 31 flat-racing Thoroughbreds with lameness (grade 1-3/5) localised to the carpus by intra-articular analgesia were selected. Following a radiological assessment of the carpi confirming the absence of fragment/fracture, the horses were randomly assigned for intra-articular treatment with either 2ml of 2.5% PAAG, 12mg TA or 20mg HA (followed by two further intravenous treatments of 40mg, at weekly intervals in the HA group only), by a treating veterinarian. All horses were rested for 48 hours post-treatment and then re-entered an unaltered training regimen. Subsequent examinations at 2, 4, and 6 weeks were performed by a blinded examining veterinarian for all groups, while horses treated with 2.5% PAAG were also monitored up to 12 weeks for recurrence of lameness.

Significantly more joints treated with the 2.5% PAAG were lame free (83%) at 6 weeks compared to TA (27%; p=0.007) and to HA (40%; p= 0.04). There was no significant difference between TA and HA groups at any time. All the joints treated with 2.5% PAAG that were lame free at 6 weeks (10/12) were still lame-free at 12 weeks. In conclusion, the study showed that treatment with 2.5% PAAG led to statistically superior results compared to TA or HA in the management of middle carpal joint lameness in flat-racing Thoroughbreds, with therapeutic effects persisting up to 12 weeks.

These results were consistent with another positive control study presented at ECVS in 2014(4) that compared the efficacy of 2.5% PAAG (Arthramid® Vet) vs a combination of TA/HA treated fetlock joints in 40 horses. Inclusion criteria included intraarticular analgesia, radiology and MRI. Of the 40 horses meeting the inclusion criteria, 20 were assigned to the treatment group, and 20 to the control group. At 1, 3 and 6 months, estimated proportions of sound horses were 55%, 65% and 75%, respectively in the 2.5% PAAG treated group, and 15%, 40% and 35%, respectively in the TA/HA treated control group. This study concluded that 2.5% PAAG demonstrated a significant reduction in lameness when compared with horses treated with TA-HA (p=0.001), with no adverse reactions. 

It appears from these and other available studies, that 2.5% PAAG is an effective and safe treatment and that it has superior and longer lasting effects than TA. Therefore veterinarians should be considering its use as a first line treatment and earlier in the disease process than previously thought.

Concomitant use of TA and 2.5% PAAG (Arthramid® Vet).

There are no studies to date that have assessed if the joint capsule augmentation resulting from administration of 2.5% PAAG has any potential influence on excretion rates of intra-articular corticosteroids or drug detection times. Although the fact that administration of 2.5% PAAG also results in the formation of a new and hypercellular synovial membrane and increased angiogenesis(5) means it might be expected to improve clearance rates. To our knowledge, and with thousands of doses of 2.5% PAAG now administered in racing and performance horses worldwide, no reports of prolonged drug detection times have been recorded. 

Regardless, the simultaneous use of corticosteroids with 2.5% PAAG may even appear, at least at first, to be counterintuitive; the 2.5% PAAG bio-scaffold is ideal for fibroblasts promoting cell migration and vessel infiltration. Conversely, TA has been shown to decrease both cellular proliferation and collagen production by dermal fibroblasts. Whilst to our knowledge this has not been demonstrated in the joint, it is difficult to see why it wouldn't have the same influence on synovial fibroblasts. The strategy of using 2.5% PAAG is to promote disease modification, and if we consider the impact of OA on intimal fibroblasts and the decreased action/ capability for these cells to respond to inflammation, this might not be able to be achieved if we are inhibiting the very cells we are trying to encourage. That said, we acknowledge that concurrent use of corticosteroids and 2.5% PAAG does take place and, anecdotally at least, clinicians we have talked to believe they achieve similar results to using 2.5% PAAG alone. Some support for this is found in a retrospective case series report of 804 joints in 341 horses(6), where 70/80 (87.5%) and 232/261 (88.9%) of those treated with 2.5% PAAG plus ancillary treatment, or with 2.5% PAAG alone respectively, achieved their anticipated outcome within two months, although this data has not undergone peer review.

Therefore, from a clinical perspective at least, it appears logical to recommend using 2.5% PAAG alone and as early as practical to modify the disease process and restore joint function. Then at a later time (at least 2 weeks) using corticosteroids if or when necessary to manage any ongoing inflammatory process and where the clinician believes a clinical benefit can be achieved given their knowledge of the disease process going on in the joint at the time. This would have the added advantages of using the likes of TA within normal drug withhold times and reducing the use of corticosteroids overall. This may serve to even address some of the ongoing agency and animal welfare concerns of current usage patterns of corticosteroids across performance equine populations. 

How are we using 2.5% PAAG and TA?

We are encouraging clients more and more to use 2.5% PAAG (Arthramid® Vet) as a first choice treatment once a diagnosis of osteoarthritis (including synovitis, capsulitis, meniscal injury and subchondral bone injury) has been confirmed through intraarticular analgesia +/- secondary imaging. Although at first it might appear expensive, owners are increasingly recognising the value of a better long-term reduction in lameness and the benefits of a decrease in repeated treatments and, ongoing drug or supplement intakes. 

Clinical studies show that tissue integration and subsequent augmentation of the joint capsule with 2.5% PAAG takes between 2 and 4 weeks to occur, although a response to treatment can be seen earlier than that in some cases; in our experience animals typically show a gradual reduction in lameness during the first week after treatment and a concurrent reduction in synovitis and reaction to passive flexion. This continues to improve over the ensuing weeks. 

By 4 to 6 weeks no further improvement is expected. Re-examination at 4 to 6 weeks is therefore indicated to either administer a second dose - in those that have only partially responded (about 15% of cases) or to reassess the accuracy of our diagnosis. In this respect and due to its long lasting effect, we find it best to treat the animal during periods of reduced exercise demands or earlier in the animals training programme than what us and our owners, would normally have considered previously. This also allows us to pro-actively manage the animal with the client and more at the beginning of the competition season, rather than having to be reactive half way through or when higher demands for competition are placed on the horse, the rider and the veterinarian. 

In cases with more marked joint inflammation (synovitis/ capsulitis) we typically also prescribe NSAID’s (typically Meloxicam) for 3 to 5 days following treatment with the 2.5% PAAG. In our experience this can oftentimes give a better clinical response, presumably because it is reducing the inflammatory profile of the joint whilst the 2.5% PAAG itself is undergoing the tissue integration process.

In extremely severe and/or acute osteoarthritis cases (marked synovitis/ capsulitis) or when competition schedules mean a 2 to 4 week period is not available to allow a response to treatment with the 2.5% PAAG, we will administer corticosteroids (TA) for its immediate anti-inflammatory benefits. However, this is always with the view that we will still administer 2.5% PAAG as soon as the time in the competition schedule allows and ideally not within 2 weeks of TA administration, so as to avoid any potential interference with the integration process, as described earlier. 

Conclusion

Equine veterinarians have a range of options to treat lameness in horses caused by osteoarthritis (OA) and practitioners must use all means at their disposal to ensure horses are exposed to the absolute least amount of discomfort and pain, and potential for injury, while under their care. 

Whilst corticosteroids remain a popular treatment choice, primarily for their potent anti-inflammatory effects and the fact that they are relatively inexpensive and easily accessible, non-steroidal intra-articular drugs (NSAID’s) are used more by experienced equine practitioners and as a first choice treatment earlier on in the disease process because of their disease modifying potential. Whilst we recognise that different clients may have varying expectations and financial constraints, it is our responsibility as veterinarians to offer all of the alternative treatment options available for a specific disease. 

2.5% PAAG (Arthramid® Vet) comes in a ready-to-use pre-filled 1ml syringe making it easily accessible, and it is now approved in the US for veterinary (and human) use. In our experience, once a horse has been treated with 2.5% PAAG it is lame less often and requires less repeated treatments with corticosteroids and ongoing and oftentimes expensive drug and supplement intake. From a client outcome perspective this has been a ‘game-changer’ in how we manage joint lameness in our practice and we can only see its use amongst equine veterinarians increasing as knowledge and an understanding of its benefits increases. 

References

1. AA Alvarez, LH Boone, AP Braim, JS Taintor, F Caldwell, JC Wright, AA Wooldridge (2020).  A Survey of Clinical Usage of Non-steroidal Intra-Articular Therapeutics by Equine Practitioners. Front Vet Sci; 7:579967
2. CW McIlwraith (2016). Corticosteroids. In:  McIlwraith CW, Frisbie DD, Kawcak CE and van Weeren PR, editors. Joint Disease in the Horse 2nd Edition, Missouri: Elsevier, p 202-214. 
3. LT de Clifford, JN Lowe, CD McKeller, C McGowan, F David. (2021). A double-blinded positive control study comparing the relative efficacy of 2.5% polyacrylamide hydrogel (PAAG) against triamcinolone acetonide (TA) and sodium hyaluronate (HA) in the management of middle carpal joint lameness in racing Thoroughbreds. J Eq Vet Sci; 103780. Available online https://www.sciencedirect.com/...
4. A Tnibar, H Schougaard, M Koene, B Markussen (2014). A controlled clinical trial on the efficacy of an intra-articular polyacrylamide hydrogel in horses with osteoarthritis. Proceedings of the European College of Veterinary Surgeons Annual Scientific Meeting; 3-5th July, Copenhagen, Denmark.
5. LH Christensen, L Camitz, KE Illigen, M Hansen, R Sarvaa, PG Conaghan. (2016). Synovial incorporation of polyacrylamide hydrogel after injection into normal and osteoarthritic animal joints. Osteoarthritis and Cartilage; 24: 1999-2002. 
6. UK Case Series; Available online at https://arthramid.com.au/uk-eq...