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Joint Medication: Part 3 - Commonly used joint medications



OK - Just putting this out there at the beginning of this post, this is a long read. I wanted to provide an all encompassing guide to the routinely available options for joint injections. Injections into joints are routinely called intra-articular injections. Although your choice might be driven by what is financially viable, insurance policy or availability of certain medications and services in your area, knowledge is power.


Scientific data is constantly evolving. Things change, and as a result, when new, additional or contradictory information is available, I will try to update the blog. Equally, if someone knows of a scientific study which would add to the blog, please send it my way.


A lot of the studies involved in this blog post are based on injection into a single type of joint. The medication may work better, or worse, in another joint. None of the studies involved provided the owners with regimented rehabilitation plans based on which area was being injected. This MUST have a huge influence on the success of the medication. This is why I call joint injections LIQUID PLASTERS. I truly believe that hard work before and after joint injections significantly improves the outcome.


This also influences the most frequently asked question associated with joint injections: ‘How long will the medication last for? Will I have to repeat it again?’

Nobody can ever give you an accurate time frame. It depends on the severity of the lesions, and again, the work which you are prepared to put in. Working with someone that truly understands the biomechanics of your horse’s joints can really help to get you on the right track.


Every case is specific, and my preferred treatment would be based on a multitude of factors discussed during consultations. This guide in mainly to help you understand how the treatment is supposed to help your horse.


 

The risk associated with every type of joint injection - flare and sepsis (joint infection)


Unfortunately, an occasional risk of joint injections involves reactions to the procedure and medication injected. This may be a:

  • Flare up - non infectious process and generally resolves with pain relief, more commonly after injection of hyaluronic acid (1).

  • Sepsis - infectious disease due to introduction of bacteria or fungi into the joint (1). May require surgery to remove the infection.

Can risk of sepsis be decreased?

A sterile scrub should be performed before any joint is injected. A 2021 study (2) showed that the frequency of sepsis is about 0.04%, with no difference between joint injections performed in the field or in hospital settings, or when antibiotics were combined with the medication.

The most commonly used antibiotic is amikacin, however, it has recently been found to cause joint damage as well (3).


 

Steroids

The body naturally produces corticosteroids. Corticosteroids are strong anti-inflammatories, decreasing inflammation both in the short and long term. Although the short term change is pretty obvious, long term change is achieved through gene regulation (4). This basically means that the increased load of steroids affects the body to subsequently produce more anti-inflammatories. Therefore, decreased inflammation is due to the steroids injected and their effect on the rest of the body.


The two main steroids used are called Triamcinolone (TA) and Methylprednisolone Acetate (MPA).

  • TA is detected within the joint for just 10 days after administration, and is almost undetectable in the blood after 48 hours (4).

  • MPA gets broken down to methylprednisolone (MP) within the joint, and remains detectable within the joint for 5-39 days. Although MPA is not detected in the blood, MP can be detected for 1-30 days (4).


What does this mean?

The FEI outlines the importance of anti-doping to promote a clean and fair sport. Because of how long TA and MP last in the blood for, the withdrawal period (time between injection and when a horse can compete) is 7 days for TA and 28 days for MPA.

A full list of detection times can be found here: https://inside.fei.org/system/files/FEI%20Detection%20Times%202018_0.pdf


Do they have any negative effects?

  1. In the joint, MPA has negative effects on articular cartilage (5). This does not appear to be the case with TA (6).

  2. Laminitis - scientific evidence shows that appropriate TA dosage administered into a joint does not increase the risk of laminitis in healthy horses (7). I have not been able to find a paper regarding MPA or use of intra-articular steroids in horses with hormonal diseases, such as Cushing’s or Equine Metabolic Syndrome (EMS).


Any other positive effects?

Intra-articular administration of TA (8) and MPA (9) also improve lung function in horses with severe asthma, and this lasts longer with TA. No vet would ever advocate using intra-articular steroids to treat asthma.


Which steroids are generally injected into which joints?

Due to the degenerative side effects of MPA, it is usually injected into smaller joints, like the tarsometatarsal joint, to promote ankylosis (fusion), therefore decreasing pain.


After the 2nd blog about joint communication, do we need to treat every joint compartment?

Every vet preference is based on their own personal experience and success rates. However, studies show that steroids always transfer between the tarsometatarsal and distal intertarsal joints (10) and between the coffin joint and navicular bursa (11).


 

Lack of joint lubrication plays a significant role in the pathogenesis of osteoarthritis (OA).


Two important molecules produced by synovial lining cells (the inside of the joint) are called hyaluronic acid and lubricin. They help to protect and maintain the integrity of the articular cartilage surfaces in synovial joints by reducing friction. As part of the OA complex, the synovial fluid (fluid within the joint) does not remain as visco-elastic, meaning that it loses its ability to properly provide shock absorption.

Apart from injection of the substances which are generally naturally created by the joint, a synthetic alternative is also available.


Hyaluronic Acid (HA)

HA is present in the skin, connective tissue, eyes and synovial fluid, and its main responsibility is in pulling water into that space. It is a naturally occurring unbranched non-sulfated glycosaminoglycan (semi-important to remember for the 4th blog in the series).

HA functions in a number of ways (12), mainly in reducing friction, decreasing pain, cartilage damage and inflammatory markers. When injected, it is said to improve visco-elasticity, decrease inflammation and increase natural production of hyaluron.


But does this hold up scientifically?

The issue with this naturally occurring product is just that. Because it develops naturally, it is metabolized and broken down in a natural way.

Subsequently, when HA is administered intra-articularly (IA), it dissipates out of the joint within 14–18 hours before being rapidly eliminated from the body (13). This means that it has a very limited window to provide benefit.

A number of studies exist which show the effect on inflammation in joints when HA is used alone or in combination with TA (14) or MPA (15).


The big question: Does HA used intra-articularly in combination with steroids actually improve lameness?

Unfortunately, not many studies exist to show this. The study I found looked at only 80 horses which blocked to one particular joint (16). The horses then either received TA or a combination of TA and HA into that joint. They were reassessed after 3 weeks and 87.8% of horses which received only TA had improved by 2 lameness grades (out of 5), compared to 64.1% in the combination group. By 3 months, only half of the horses in the study, regardless of which group they were in, had returned to the same level of work.


What do these results actually mean though?

So many variables exist within the study - the age, breed, discipline, rehab routine, paraprofessional help after injection. However, the relative lack of initial lameness change and lack of improvement in the combination group compared to the TA group at the 3 month point shows that intra-articular HA may not be the best use of resources. Further studies are definitely needed to show that it should be a mainstay in joint treatment, however, a recent systemic review also highlighted its lack of long term effectiveness (17).


Can HA be used in another way?

Keep an eye out for the 4th part of this blog series to find out.


Lubricin

Lubricin also helps to maintain visco-elasticity, however, there are currently an insignificant number of studies into its intra-articular use and subsequent long term benefit.



Polyacrylamide - Arthramid

Arthramid is a synthetic polyacrylamide hydrogel (PAAG), consisting of 97.5% sterile water and 2.5% PAAG. It has a similar structure to HA, however, as it is non-degradable, has a significantly longer effect.


A 2021 study (18) of TB horses with middle carpal joint lameness showed that horses which received PAAG had an 83% chance of being lameness free at 6 weeks, as opposed to 27% that received TA and 40% that received HA. This is a great case study as all the horses were in flat race training and the lameness was localized to the same joint in every horse. I know what the next question is going to be - How is the HA group better than the TA group? - I will cover this in the 4th part of this blog series.




So how does it work? (19)

The PAAG incorporates into the joint lining (synovial membrane), reducing the exposure of the cells which produce joint fluid (synoviocytes) to the inflammatory markers within a diseased joint. Gradually, blood vessels start to develop around the attached PAAG, creating a supportive network. By day 14, synovial cells start to infiltrate this network, with a noticeable rejuvenation of the synovial membrane within 30 days. This has been shown to last for 2 years (20).


The study also showed that the gel was highly unlikely to cause any long term side effects, despite being present for an extended period of time.



Due to this mechanism of action, case selection is essential. PAAG should only be used in cases with a significantly positive intra-articular block. Owners should not expect an immediate improvement, rather one which begins at 4-6 weeks post injection. Some horses (about 15%) may need a second dose.


Due to its properties, I would only expect it to access different joint compartments if there was physical communication. As discussed in the second part of this blog series, it is very rare for owners to know about this communication. This could mean that the gel remains concentrated, and therefore, you would think, more effective in one horse, but more diluted, and therefore, possibly less effective in other horses. These horses may need the second dose. It is also why it may be less effective in larger joints, like the stifle, unless a larger volume was administered. Further studies are needed to help to determine whether this holds true.


 

Biological products


In a recent survey of over 400 vets, they found that the best responding joints to biological therapy were the stifle, followed by the fetlock and coffin joint (21). But what are biological products and how do they work?


A biological product implies that it is a product derived from animal origin, namely from a horse. This can fall into two categories:

  • Autogenous - product comes directly from the horse being treated.

  • Allogeneic - product is produced from a pool of horses and commercially sold.


The biological products are obtained from a few categories:

  • Blood

    • Autogenous

      • PRP

      • IRAP

      • Pro-Stride

      • Alpha-2 Macroglobulin (ɑ2M)

    • Allogeneic

      • Arti-cell forte

  • Fat

  • Bone Marrow


Blood products


These biological products are harnessed in extremely similar ways, both starting with blood withdrawn from the patient (or donor patients for Arti-cell Forte). Depending on which product is being produced, a commercially available kit is used to process the blood, either by:

  1. Spinning it down to separate different blood components - PRP, Pro-Stride and ɑ2M.

  2. Storing it in a specific way before spinning it down - IRAP.

  3. Harnessing and multiplying specific cells within blood called mesenchymal stem cells which specifically target cartilage repair - Arti-cell Forte.



Is this important to know? Not particularly, however, not every vet practice may have every processing option. They may therefore not offer particular treatment options which might be better for your horse.


Platelet rich plasma (PRP)

Platelets are tiny cells in blood which have granules filled with growth factors (help with healing). They therefore stimulate tissue healing. PRP consists of 4.7 times as many platelets as blood. Intra-articular treatment with PRP causes an initial, short synovial inflammatory reaction, followed by a significant increase in local growth factor concentrations.

PRP is more commonly used to treat tendon and ligament lesions as it can be easily injected into core lesions under ultrasound guidance.

Interleukin-1 Receptor Antagonist Protein (IRAP)

An inflammatory response during joint trauma is triggered mainly by a naturally produced compound called Interleukin-1 (IL-1), resulting in joint destruction. IRAP uses a horse’s own anti-inflammatory protein found in the blood to counteract the destructive effects, by blocking the action of IL-1.

The blood is stored in a tube with glass beads for 24 hours. The glass beads provide a larger surface area. Two types of IRAP can be produced: IRAP and IRAP 2. The difference between the two is that heparin (a blood thinner that prevents blood clots) is mixed with the blood in the tube - this results in the increased production of IRAP, as well as cytokines (small cells which stimulate an improved immune response). After the 24 hours, the blood product is spun down to collect the beneficial portion which can then be injected into the joint.

IRAP 2 (without the heparin) has significantly higher levels of the anti-inflammatory protein, therefore providing better protection to IL-1 (22).

It is mainly used for joints with synovitis, capsulitis, and osteoarthritis. A common treatment regimen would include treatment of the affected joint every 7-10 days for 3-5 treatments.


Pro-Stride Injection

Pro-stride is kind of like a PRP and IRAP combo. It is initially prepared in the same way as PRP. The PRP portion is then put into a commercially available device, and spun down again to create a very concentrated Autologous Protein Solution (APS). APS contains anti-inflammatory proteins, including IRAP. The whole process takes about 20 minutes and the centrifuge (machine which spins down the blood) is portable, meaning that it can be performed anywhere.

Unlike with IRAP, only a single injection is required, meaning that it is a one-time visit.

APS does seem to have better results in horses with low grades of lameness and without significant arthritic changes, with improvement in lameness lasting for about a year (23).

Alpha-2 Macroglobulin (ɑ2M)

Blood is withdrawn in a commercially available kit before it is spun down to concentrate a molecule called Alpha-2 Macroglobulin. ɑ2M inhibits molecules responsible for breaking down cartilage by ‘trapping’ them.

The only research currently available about how effective ɑ2M is is provided by the company which manufactures the kits to produce ɑ2M. Their research showed mainly positive responses, with a few horses requiring second doses which were collected and frozen during the initial processing (24). I would be really interested in more scientific evidence where a conflict of interest is not present.


Mesenchymal stem cells (MSCs) products



Before discussing the next 3 treatment options, it is really important to have a basic understanding of MSCs. I like to compare these cells to chameleons, due to their ability to change/ develop into other cells based on the environment which they are in. MSCs can mainly be obtained from blood, bone marrow, fat and umbilical tissue. Due to this ability to differentiate into other cell types, they can play a key role in regenerative therapy.

Arti-cellⓇ forte

This product is allogeneic. This means that blood is withdrawn from donor horses that are genetically ‘good healers’. The MSCs withdrawn from the donor blood and cultured in a lab.

Many big words but what do they mean? Stem cells are special cells which have the ability to develop into any type of cell in the body. Under specific conditions, they can be ‘cultured’ to be selectively developed into chondrogenic (cartilage forming) cells. This results in the formation of a uniform, concentrated solution of cells which can be injected into a joint.

Arti-cell forte must be transported in liquid nitrogen. Before injection, it is thawed and combined with allogeneic plasma (a blood component).

A 2109 study (25) showed that by week 6 post injection, 30% were competing at the same level as before and a further 42% were working at training level, compared to 0 horses which received a placebo instead. 84% of horses were training or competing at the same level as before their orthopedic issues after 1 year.

Happy Fat

Adipose tissue provides a readily available source of MSCs. An initial study showed negative results when fat was cut out and injected into a joint, as this caused more inflammation (26).

A more recent study, in which micro-fat was harvested and combined with PRP, showed extremely positive results in late stage joint disease (27), with PRP improving MSC proliferation and chondrogenic differentiation. In the same study, the 8 horses treated had all been retired from competition and 7 of them returned to competition or high level training within 5-10 months.


Bone Marrow Derived MSCs

Bone marrow for orthopedic use is obtained from the pelvis. If a horse has blood coagulation disorders, a sample of bone marrow is generally obtained from the sternum.

The bone marrow aspirate is rich in macrophages. These are white blood cells which are responsible for reducing inflammation and maximize tissue repair by repairing defects in the cartilage (28).

Studies into efficacy of bone marrow derived MSCs are promising (29), however, as with most treatment options, further scientific data and long term outcomes would be very welcome.


 

Arthrodesis

This is the process of fusing a joint. This can be done surgically with plates or through the injection of 70% ethyl alcohol. The decision is based on the type of joint to be fused and the financial situation of the owner.

The most commonly performed chemical arthrodesis is that of the distal hock joints. As explained in the second part of this blog series, about 3% of the distal hock joints communicate with the larger, proximal joints. This communication MUST BE ruled out before the alcohol is injected. This is done with contrast dye.


A study of 16 horses showed that 50% of normal horses were radiographically fused by 4 months and 94% were fused by 12 months. They were all sound by 12 months (30).



Chemical arthrodesis of the pastern joint is also available if surgical arthrodesis is financially not viable. This is not as successful, with 50% of horses becoming sound and a further 38% with an improved lameness score (31).


 

Conclusion

New scientific studies about joint medication are published on an extremely regular basis. As discussed earlier, vets usually opt for treatment based on their own experience of certain conditions, equipment available and financial capabilities of the owner.

Studies are extremely frustrating due to the general lack of a fixed routine post treatment. I do believe that success rates would be different, and better, if bespoke rehabilitation plans were laid out and subsequently followed.

References

  1. Singer, E., 2008. Clinical challenges of persistent articular sepsis. Equine Veterinary Education, 20(7), pp.353-356.

  2. Krause, D., Pezzanite, L., Griffenhagen, G. and Hendrickson, D., 2021. Comparison of equine synovial sepsis rate following intrasynovial injection in ambulatory versus hospital settings. Equine Veterinary Journal,.

  3. Pezzanite, L., Chow, L., Soontararak, S., Phillips, J., Goodrich, L. and Dow, S., 2020. Amikacin induces rapid dose‐dependent apoptotic cell death in equine chondrocytes and synovial cells in vitro. Equine Veterinary Journal, 52(5), pp.715-724.

  4. McIlwraith, C., 2010. The use of intra-articular corticosteroids in the horse: What is known on a scientific basis?. Equine Veterinary Journal, 42(6), pp.563-571.

  5. Frisbie, D., Kawcak, C., Baxter, G., Trotter, G., Powers, B., Lassen, E. and McIlwraith, C., 1998. Effects of 6a-methylprednisolone acetate on an equine osteochondral fragment exercise model. American Journal of Veterinary Research, 59(12), pp.1619-28.

  6. Frisbie, D., Kawcak, C., Trotter, G., Powers, B., Walton, R. and McIlwraith, C., 1997. Effects of triamcinolone acetonide on an in vivo equine osteochondral fragment exercise model. Equine Veterinary Journal, 29(5), pp.349-359.

  7. Haseler, C., Jarvis, G. and McGovern, K., 2020. Intrasynovial triamcinolone treatment is not associated with incidence of acute laminitis. Equine Veterinary Journal, 53(5), pp.895-901.

  8. Bessonnat, A., Picotte, K. and Lavoie, J., 2020. Intra‐articular triamcinolone acetonide improves lung function in horses with severe asthma. Equine Veterinary Journal, 52(1), pp.131-135.

  9. Millares‐Ramirez, E., Picotte, K. and Lavoie, J., 2021. Pulmonary response of severely asthmatic horses after intra‐articular administration of methylprednisolone. Equine Veterinary Journal, 53(1), pp.78-84.

  10. Serena, A., Schumacher, J., Schramme, M., Degraves, F., Bell, E. and Ravis, W., 2005. Concentration of methylprednisolone in the centrodistal joint after administration of methylprednisolone acetate in the tarsometatarsal joint. Equine Veterinary Journal, 37(2), pp.172-174.

  11. Boyce, M., Malone, E., Anderson, L., Park, S., Godden, S., Jenner, F. and Trumble, T., 2010. Evaluation of diffusion of triamcinolone acetonide from the distal interphalangeal joint into the navicular bursa in horses. American Journal of Veterinary Research, 71(2), pp.169-175.

  12. Gupta, R., Lall, R., Srivastava, A. and Sinha, A., 2019. Hyaluronic Acid: Molecular Mechanisms and Therapeutic Trajectory. Frontiers in Veterinary Science, 6.

  13. Pierce SW. Efficacy of orally administered sodium hyaluronate gel in the racing thoroughbred. In: Balazs EA, Hascall VC. editors. Hyaluronan 2003 Proceedings. Chapter 6. Musculoskeletal System. Cleveland, OH: Matrix Biology Institute, (2004) p. 1–4.

  14. Schaefer, E., Stewart, A., Durgam, S., Byron, C. and Stewart, M., 2009. Effects of sodium hyaluronate and triamcinolone acetonide on glucosaminoglycan metabolism in equine articular chondrocytes treated with interleukin-1. American Journal of Veterinary Research, 70(12), pp.1494-1501.

  15. Yates, A., Stewart, A., Byron, C., Pondenis, H., Kaufmann, K. and Constable, P., 2006. Effects of sodium hyaluronate and methylprednisolone acetate on proteoglycan metabolism in equine articular chondrocytes treated with interleukin-1. American Journal of Veterinary Research, 67(12), pp.1980-1986.

  16. de Grauw, J., Visser-Meijer, M., Lashley, F., Meeus, P. and van Weeren, P., 2015. Intra-articular treatment with triamcinolone compared with triamcinolone with hyaluronate: A randomised open-label multicentre clinical trial in 80 lame horses. Equine Veterinary Journal, 48(2), pp.152-158.

  17. da Silva Xavier, A., da Rosa, P., de Brum Mackmill, L. and Roll, V., 2021. An assessment of the effectiveness of hyaluronic acid and polyacrylamide hydrogel in horses with osteoarthritis: Systematic review and network meta-analysis. Research in Veterinary Science, 134, pp.42-50.

  18. ​​de Clifford, L., Lowe, J., McKellar, C., McGowan, C. and David, F., 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. Journal of Equine Veterinary Science, 107, p.103780.

  19. Christensen, L., Camitz, L., Illigen, K., Hansen, M., Sarvaa, R. and Conaghan, P., 2016. Synovial incorporation of polyacrylamide hydrogel after injection into normal and osteoarthritic animal joints. Osteoarthritis and Cartilage, 24(11), pp.1999-2002.

  20. Tnibar, A., Schougaard, H., Camitz, L., Rasmussen, J., Koene, M., Jahn, W. and Markussen, B., 2015. An international multi-centre prospective study on the efficacy of an intraarticular polyacrylamide hydrogel in horses with osteoarthritis: a 24 months follow-up. Acta Veterinaria Scandinavica, 57(1).

  21. Zanotto, G. and Frisbie, D., 2021. Current joint therapy usage in equine practice: changes in the last 10 years. Equine Veterinary Journal, 0, pp.1-7.

  22. Hraha, T., Doremus, K., McIlwraith, C. and Frisbie, D., 2011. Autologous conditioned serum: The comparative cytokine profiles of two commercial methods (IRAP and IRAP II) using equine blood. Equine Veterinary Journal, 43(5), pp.516-521.

  23. Bertone, A., Ishihara, A., Zekas, L., Wellman, M., Lewis, K., Schwarze, R., Barnaba, A., Schmall, M., Kanter, P. and Genovese, R., 2014. Evaluation of a single intra-articular injection of autologous protein solution for treatment of osteoarthritis in horses. American Journal of Veterinary Research, 75(2), pp.141-151.

  24. Alpha2EQ. 2022. Research. [online] Available at: <https://alpha2eq.com/research/> [Accessed 15 March 2022].

  25. Broeckx, S., Seys, B., Suls, M., Vandenberghe, A., Mariën, T., Adriaensen, E., Declercq, J., Van Hecke, L., Braun, G., Hellmann, K. and Spaas, J., 2019. Equine Allogeneic Chondrogenic Induced Mesenchymal Stem Cells Are an Effective Treatment for Degenerative Joint Disease in Horses. Stem Cells and Development, 28(6), pp.410-422.

  26. Frisbie, D., Kisiday, J., Kawcak, C., Werpy, N. and McIlwraith, C., 2009. Evaluation of adipose-derived stromal vascular fraction or bone marrow-derived mesenchymal stem cells for treatment of osteoarthritis. Journal of Orthopaedic Research, 27(12), pp.1675-1680.

  27. Bembo, F., Eraud, J., Philandrianos, C., Bertrand, B., Silvestre, A., Veran, J., Sabatier, F., Magalon, G. and Magalon, J., 2016. Combined use of platelet rich plasma and micro-fat in sport and race horses with degenerative joint disease: preliminary clinical study in eight horses. Muscles, Ligaments and Tendons Journal, 6(2), pp.198-204.

  28. Menarim, B., MacLeod, J. and Dahlgren, L., 2021. Bone marrow mononuclear cells for joint therapy: The role of macrophages in inflammation resolution and tissue repair. World Journal of Stem Cells, 13(7), pp.825-840.

  29. Bertoni, L., Jacquet-Guibon, S., Branly, T., Desancé, M., Legendre, F., Melin, M., Rivory, P., Hartmann, D., Schmutz, A., Denoix, J., Demoor, M., Audigié, F. and Galéra, P., 2021. Evaluation of Allogeneic Bone-Marrow-Derived and Umbilical Cord Blood-Derived Mesenchymal Stem Cells to Prevent the Development of Osteoarthritis in An Equine Model. International Journal of Molecular Sciences, 22(5), p.2499.

  30. Shoemaker, R., Allen, A., Richardson, C. and Wilson, D., 2006. Use of intra-articular administration of ethyl alcohol for arthrodesis of the tarsometatarsal joint in healthy horses. American Journal of Veterinary Research, 67(5), pp.850-857.

  31. Caston, S., McClure, S., Beug, J., Kersh, K., Reinertson, E. and Wang, C., 2013. Retrospective evaluation of facilitated pastern ankylosis using intra-articular ethanol injections: 34 cases (2006-2012). Equine Veterinary Journal, 45(4), pp.442-447.


Image reference

The Arthramid image was obtained from the 2019 white paper, accessible through their website on 15/3/22.




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