Introduction
The management of joint health in horses, particularly in the context of osteoarthritis (OA), is a critical aspect of veterinary medicine.1,2 Osteoarthritis is a progressive joint disease initiated by synovitis, driven by inflammatory mediators within the joint microenvironment, which initiates a cascade of pathological changes, including articular cartilage degradation, subchondral bone changes, osteophyte formation, and joint capsule thickening or fibrosis. These changes eventually involve periarticular structures such as ligaments, menisci, and surrounding muscles, and involvement of these structures culminates in pain, reduced mobility, and loss of joint function.3–8 The metacarpophalangeal joint (MCPJ) in horses, also known as the fetlock joint, is a well-defined study model for OA, as it is a high-motion joint and the most common to be affected by spontaneous OA and overload arthrosis.8–13 The prevalence and economic impact of OA in horses are substantial,14 with the disease affecting millions of horses and incurring direct costs that exceed billions of dollars annually.3 Effective management of OA in horses is crucial, and intra-articular (IA) treatments have been widely adopted in an attempt to mitigate the signs and progression of the disease, positively impacting welfare and performance.3,5,8,9,15–22
A promising treatment for OA in horses has emerged over the last 15 years: 2.5% polyacrylamide hydrogel (2.5% iPAAG).21,23–28 An international multicenter prospective study24 in 2015 involving 43 horses demonstrated the long-term benefits of 2.5% iPAAG in OA management, with 90% of owners expressing satisfaction and 82.5% of treated horses remaining sound at a 2-year follow-up. Lowe et al21 report that 2.5% iPAAG integrates into the synovial membrane within 14 days, enhancing joint capsule elasticity and reducing overall joint stiffness, and Tnibar28 reports that 2.5% iPAAG does not affect proinflammatory cytokines and shows no signs of neurotoxicity or fibrosis within the joint. Scanning electron microscopy has shown that 2.5% iPAAG forms a stable 3-D scaffolding structure that supports tissue integration, contributing to its long-term efficacy.21 No adverse events (AEs) have been reported in equine clinical studies that use 2.5% iPAAG.21,23–28 However, it should be noted that there exists a conference abstract28,29 from the Veterinary Orthopedic Society that reports a single instance of an undefined transient AE in 1 horse, which occurred after the second of 2 treatments. The positive outcomes and low rate (estimated at 0.04%) of AEs make 2.5% iPAAG a common option for management of OA in horses.21,28
Betamethasone esters, utilized in the form of betamethasone sodium phosphate and betamethasone acetate (BME), have been prominent corticosteroids for IA injection in the management of OA in horses over the past 30 years.5,9,16,20,30,31 This formulation combines a rapid-acting, water-soluble component with a prolonged-release lipid-soluble component, providing both immediate and sustained anti-inflammatory effects.32 Clinical studies30,31 have demonstrated the efficacy of BME in reducing pain and inflammation in arthritic synovial joints in horses. The mechanism of action of BMEs involves the inhibition of key inflammatory mediators, such as IL-6,33 IL-1, and tumor necrosis factor-α; stabilization of lysosomal membranes; reduction of capillary dilation; and inhibition of the prostaglandin cascade, which are crucial in the pathogenesis of OA.9,17 According to the package insert,32 a negative control, randomized, masked field study found that 75.53% of 119 horses treated with BME showed clinical success with improved lameness scores 5 days after injection, compared to 52.52% of 120 horses that received a saline control. The use of BME is generally associated with a favorable safety profile, although potential AEs have been noted.5,9,16,20,30–32 Reported AEs from a field trial involving 239 horses, which included BME (n = 119) and a saline control (120), included increased joint effusion (15%), increased lameness (6.7%), loose stool (5.9%), increased heat in the joint (2.5%), agitation/anxiety (4.2%), delayed swelling of the treated joint (2.5%), inappetence (3.4%), dry stool (1.7%), excessive sweating (0.8%), acute non–weight-bearing lameness (0.8%), and laminitis (0.8%).32 These effects highlight the importance of monitoring for systemic absorption, which can mask symptoms of joint infections and exacerbate laminitis in susceptible horses.34–36 Overall, the long-standing clinical use of BME, supported by substantial clinical data, underscores its role in effectively managing OA symptoms. However, as with all corticosteroid therapies, careful consideration of potential risks and benefits is crucial, particularly concerning long-term joint health and systemic effects.
Despite the individual benefits of 2.5% iPAAG21,23–28 and BME,5,9,17,20,30,31 there is a lack of existing studies investigating their concurrent use. Concurrent injection of 2.5% iPAAG and BME could potentially offer synergistic effects, providing a more comprehensive approach to managing OA in horses. This study aimed to evaluate the safety and tolerability of concurrent IA injections. We hypothesized that concurrent IA administration of 2.5% iPAAG and BME in the right MCPJ of healthy horses would be safe and well tolerated, with no significant AEs or changes in clinical parameters compared to baseline.
Methods
Study design
This open-label safety trial evaluated the tolerability of the concurrent IA injection of 2.5% iPAAG and BME in clinically normal, sound horses. A convenience sample of 10 horses was selected. The study protocol No. 20231507 was reviewed and approved by Ethos Veterinary Health Science Consultancy Groups Animal Clinical Investigation Animal Care and Use Committee. Written informed consent was obtained from owners before enrollment.
Study facilities and timeline
Ten horses were enrolled from a therapeutic riding facility, where they were maintained under consistent care in grass pastures with run-in shelter access per location conditions. Data collection began August 1, 2023, and spanned 45 days. The screening period occurred from days –14 to –0, treatment occurred on day 0, and posttreatment evaluations were conducted by the treating veterinarian (BW) on days 0, 1, 2, 3, 7, 14, 30 and by caretakers daily (days 0 through 30). Horses remained at their home facility throughout the study, with the treating veterinarian (BW) traveling to perform all evaluations. A detailed study timeline is provided in Supplementary Table S1.
Study animals
The enrolled horses were clinically normal, healthy animals as determined by veterinary physical examination, hematology, and biochemistry (Equine Profile Plus; Zoetis), soundness examination, and forelimb flexion tests. Exclusion criteria included a body condition score other than 5/9, a history of adverse reactions to corticosteroids, evidence of lameness37 or abnormalities in any limb, at-risk status for corticosteroid-induced laminitis as determined based on a stall-side insulin test (Wellness Ready Test ≥ 20 µIU/mL; Wellness Ready Labs), systemic or dermatologic conditions that could interfere with injection safety or study participation, use of topical or systemic analgesics or anti-inflammatory drugs within 14 days prior to study enrollment, concomitant medications, and diagnosis of pituitary pars intermedia dysfunction or equine metabolic syndrome.
Intake examination
On day –14, each horse underwent a comprehensive physical examination to assess systemic health, along with soundness evaluation, MCPJ-specific clinical assessments (skin temperature, joint circumference at the level of the MCPJ), and blood collection for laboratory testing, including stall-side insulin testing. All assessments were conducted by the treating veterinarian (BW) and recorded in case report forms (CRFs).
Comprehensive physical examination
The comprehensive physical examination was conducted with the horse at rest in its stall to evaluate systemic health at screening (day –14) and again prior to sedation for treatment (day –0). Vital signs were measured at rest, including rectal temperature (°C), heart rate (HR; beats/min), respiratory rate (RR; breaths/min), mucous membranes, and capillary refill time (< 2 seconds). Lymph nodes (submandibular, prescapular, and popliteal) were palpated for enlargement or abnormalities. Eyes, ears, and nose were assessed. The heart was auscultated bilaterally for rate, rhythm, and any murmurs or arrhythmias. The lungs were auscultated bilaterally. Gastrointestinal sounds were auscultated in all 4 abdominal quadrants. The coat was visually inspected and palpated. The lower legs, including the MCPJ and surrounding structures, were palpated to assess for joint effusion, swelling outside the joint, pain, or abnormalities in soft tissue. Tendons, ligaments, and the joint capsule were evaluated for symmetry, distension, or thickening. Digital pulses were palpated for at each limb to confirm they were undetectable. Hoof health was evaluated for cracks, bruises, imbalances, or signs of inflammation.
Blood collection and stall-side insulin testing
Horses were minimally restrained, with the owner holding the haltered horse, while the veterinarian (BW) performed jugular venipuncture using a 20-gauge, 1.5-inch, multiple-sample blood-collection needle with attached needle holder for use with evacuated plastic tubes (Vacutainer; BD). Approximately 2 mL of blood was first drawn into a red-top serum separator tube, followed by an additional 2 mL into a purple-top EDTA tube. To assess the risk of corticosteroid-induced laminitis, a point-of-care insulin assay (Wellness Ready Labs) was performed with the sample from the purple-top tube per the manufacturer’s guidelines.38 Horses with an insulin level of ≥ 20 μIU/mL would have been excluded from the study due to their increased risk of corticosteroid-induced laminitis. Remaining blood samples from the purple-top and red-top tubes were submitted to an external laboratory for hematology and serum biochemistry analysis (Equine Profile Plus; Zoetis).
Joint-specific clinical assessments
The MCPJ-specific clinical assessments included skin temperature measurement and joint circumference measurement of the right fetlock at the level of the MCPJ. These parameters were evaluated to monitor localized changes at the injection site and ensure consistent tracking of joint health across all study time points. Measurements were conducted with standardized protocols to minimize variability. A handheld infrared thermometer (IR5 Dual Laser Infrared Thermometer; Klein Tools) was used for all measurements. The thermometer was positioned perpendicular to the skin surface at the injection site, maintaining a standardized distance of 30.48 cm (12 inches) as verified with a ruler. The site was inspected to ensure it was clean and free of dirt or debris. Three temperature readings were taken at each time point, and the mean was calculated and recorded as the temperature for that time point. Ambient air temperature was also recorded. After skin temperature was recorded, the right fetlock was palpated to assess for effusion or other abnormalities. Palpation included evaluation of the joint capsule and surrounding soft tissues for consistency, tenderness, or asymmetry. Following palpation, the circumference of the right fetlock at the level of the MCPJ was measured with a flexible, nonstretchable soft tape measure. The tape was positioned perpendicular to the limb axis and aligned with consistent anatomical landmarks. The proximal reference point was the distal edge of the metacarpus, while the distal reference point was the proximal edge of the pastern at the level of the proximal phalanx. The tape was placed horizontally across the widest part of the MCPJ, ensuring it was wrapped evenly around the limb without twisting or applying uneven tension. Measurements were taken while the horse was standing squarely on a level surface with weight evenly distributed. Each measurement was repeated 3 times, and the mean was calculated and recorded to the nearest half centimeter. All findings were documented in the CRFs, uploaded to each horse’s electronic medical record, and reviewed at each study time point to monitor changes from baseline.
Soundness evaluation
The soundness examination included a gait assessment at the walk and trot on a flat, firm surface. Metacarpophalangeal joint flexion tests were performed by maintaining the joint in flexion for 30 seconds, followed by jogging the horse at a trot in a straight line to assess for any signs of lameness or discomfort. Horses were also lunged at the walk, trot, and canter on a 20-m circle with soft footing, via a halter and lunge line. The evaluation confirmed the absence of observable lameness, as determined by the treating veterinarian (BW).
Treatment day
On day –0, horses underwent a second comprehensive physical examination to reconfirm systemic health and soundness prior to treatment administration. This examination followed the same protocols as the intake examination but excluded laboratory testing. Findings were documented in the CRFs. Horses were sedated with xylazine hydrochloride (100 mg/mL; 0.25 to 1 mg/kg to effect) and/or detomidine hydrochloride (10 mg/mL; 0.01 to 0.04 mg/kg to effect) administered via jugular venipuncture. The injection site over the MCPJ was aseptically prepared with a minimum of 3 alternating rounds of 7.5% povidone-iodine solution (Betadine Surgical Scrub) and 70% isopropyl alcohol. A single 1-mL dose of 2.5% iPAAG (ArthramidVet; Contura Vet Ltd) and a 1-mL dose of BME (6 mg/mL) was administered sequentially via separate syringes and 20-gauge, 1-inch needles. The right fetlock was wrapped with sterile gauze and a self-adhesive bandage, which was removed the following morning. Horses were confined to a 12 X 12-foot stall or small paddock for 3 days after injection. During this period, they underwent clinical assessments, including jogging in hand, and were hand walked daily. Findings from the treatment day, including immediate postinjection assessments for AEs, were documented in the CRFs.
Posttreatment protocol (days 0 through 30)
Case report forms—The physical examination, MCPJ assessments, and soundness examination (excluding lunging) were conducted by the treating veterinarian (BW) at every study time point (days 0, 1, 3, 7, 14, and 30) by means of the same protocols as the screening phase, with a focus on detecting deviations from the established baseline.
Adverse event monitoring—Adverse event monitoring was conducted by the treating veterinarian (BW) at every study time point (days 0, 1, 3, 7, 14, and 30) and supplemented by daily caretaker observation diaries (CODs; Supplementary Table S2). Adverse events that were monitored for included any undesirable or unexpected event or new abnormalities in clinical assessments. Caretakers were instructed to document their horse’s condition using standardized scales to ensure consistency and reliability. Comfort was assessed at rest and at the walk on a scale from 0 (no pain) to 10 (extreme pain). Observations of swelling and heat at the injection site were recorded on a categorical scale of none, slight, moderate, or severe. The caretaker was also asked to rate each horse’s overall quality of life using a 5-point Likert scale (eg, poor, fair, good, very good, excellent) documented on the COD. These observations provided a continuous record of the horse’s condition between scheduled veterinary evaluations. Caretaker observation diaries were reviewed by the veterinarian (BW) at each subsequent study time point (days 1, 3, 7, 14, and 30) following the completion of the physical examination and joint-specific assessments to cross-reference findings.
Statistical analysis
The collected data was analyzed to identify changes from baseline values. Day-to-day variability in pretreatment parameters was calculated as the absolute difference between the measurements obtained on day –14 and day –0 for each horse. Continuous variables, including HR and RR, were analyzed via repeated-measures ANOVA to evaluate mean changes across the different time points (days 0, 1, 2, 3, 7, 14, and 30). Parameters with variability, such as skin temperature and joint circumference, were analyzed statistically, while parameters with consistent values (eg, lameness grade, effusion palpation, and flexion test results) were excluded due to the lack of measurable variation. Skin temperature measurements were adjusted for ambient temperature changes, and then variation was calculated relative to the pretreatment baseline (day –0). Skin temperature variations were analyzed with paired t tests to evaluate significant differences from the baseline as compared to each study time point. For each day, the t statistic was calculated where n = 10. A 2-tailed critical t value was used to determine significance. P values were calculated for each comparison, and results were considered statistically significant if P < .05. A scatterplot was generated to visualize temperature changes over time versus ambient temperature. Right fetlock circumference at the level of the MCPJ was measured in centimeters to assess changes indicative of effusion. The Shapiro-Wilk test was employed to evaluate the normality of the pretreatment and posttreatment datasets. Based on the results of the normality test, either a parametric paired t test or a nonparametric Wilcoxon signed rank test was planned for comparing the pretreatment and posttreatment mean joint circumferences. Statistical significance was defined as P < .05. Additionally, box plots were generated to visualize the distribution. All statistical analyses were performed with statistical software.39 Results were reported with corresponding mean differences, SDs, t values, and P values. Variables with no variability (eg, lameness scale, palpation of effusion) were excluded from statistical testing and described qualitatively to confirm baseline consistency. For variables with significant findings, CIs were provided where applicable to support interpretation. No long-term follow-up was conducted as part of this study. Observations and assessments were limited to 30 days after treatment to evaluate short-term safety and tolerability outcomes.
Results
A total of 10 horses were enrolled (Supplementary Table S3), ranging in age from 11 to 24 years (median, 20 years), with 6 geldings and 4 mares. The breeds represented were 6 Quarter Horses, 2 Paint Horses, 1 Thoroughbred, and 1 Argentine Polo Horse, with heights ranging from 14.2 to 16.1 hands (median, 15.1 hands). Prior experiences included Western, English, Polo, and Mounted Cavalry disciplines. All horses met the therapeutic riding horse criteria, including soundness at all gaits, symmetrical conformation, and absence of injuries or vices.
Pretreatment
The first 10 horses screened all passed the screening phase and were enrolled in the study. On day –14, the ambient air temperature was 33.56 °C. The right fetlock skin temperature for individual horses ranged from 28.33 to 30.75 °C, while the MCPJ circumference ranged from 27.5 to 31.0 cm. Following the joint-specific assessments, soundness evaluations confirmed symmetrical and unaltered movement a\t the walk, trot, and canter in all horses. Flexion tests of the right MCPJ were negative in all cases, and each horse was considered clinically sound. Pretreatment assessments conducted on treatment day –0 before injection reconfirmed the health and soundness of all enrolled horses. All clinical parameters remained stable and within normal limits for all horses. The ambient air temperature on day –0 was 34.06 °C. The skin temperature for individual horses ranged from 29.0 to 31.2 °C, while MCPJ circumference ranged from 27 to 32.0 cm. Day-to-day variability in the measurement of skin temperature at the level of the MCPJ for each horse, during pretreatment (day –14 and day –0), adjusted for ambient temperature, ranged from a decrease of 0.41 °C to an increase of 1.55 °C (0.31 ± 0.63 °C). Day-to-day variability in the measurement of the right fetlock joint circumference at the level of the MCPJ for each horse, between day –14 and day –0, ranged from 0.0 to 1.0 cm (0.40 ± 0.32 cm). Soundness evaluations confirmed that all horses maintained symmetrical and unaltered movement at the walk, trot, and canter. Negative flexion tests of the MCPJ were observed in all cases.
Treatment
On treatment day 0, all horses were successfully sedated within the established dosage range. Arthrocentesis was performed without complications, and each horse received the full intended dose of 2.5% iPAAG and BME. No deviations from the study protocol were required. All horses tolerated the treatment with no immediate AEs observed.
Posttreatment
Throughout the 30-day postinjection observation period, all 10 horses remained sound. Clinical parameters remained within normal limits. A repeated-measures ANOVA was performed and revealed no statistically significant differences in HR (F = 0.88; P = .54) or RR (F = 1.54; P = .16). Body temperature and ambient temperature varied minimally, as presented in Supplementary Table S4. Additional monitored vital parameters remained stable throughout the study, with 0% change reported across all time points (eg, mucous membranes, digital pulses, gastrointestinal sounds, airway sounds). All parameters consistently aligned with baseline expectations for healthy and sound horses, with no deviations from normal limits observed. No systemic reactions, local reactions at the injection site, or worsening of preexisting conditions was observed. Additionally, no AEs occurred, and no signs of laminitis or corticosteroid-related complications were detected. Right MCPJ–specific clinical assessments remained unremarkable on physical examination throughout the posttreatment observation period. Subjective markers indicated that the variability was not sufficient to alter clinical examination scores (eg, from none to mild, moderate, or severe effusion), while objective markers demonstrated some day-to-day variability. Skin temperature variations were analyzed relative to the baseline (day –0) to assess significant changes at posttreatment time points. A 2-tailed critical t value of 2.262 (df = 9; α = 0.05) was used to determine significance. The baseline mean difference was 0.31 ± 0.63 °C. Paired t tests revealed significant increases on days 2, 3, 7, and 14 compared to baseline. The largest increase was observed on day 2 (1.87 ± 0.80 °C; P < .001), followed by significant elevations on day 3 (0.97 °C ± 0.74 °C; P = .02), day 7 (1.53 ± 0.78 °C; P < .001), and day 14 (1.82 ± 0.84 °C; P < .001). Days 0, 1, and 30 showed no significant differences from baseline (P > .05). These findings are summarized in Supplementary Table S5, which includes mean differences, t values, and P values for each comparison. The results demonstrated a peak in temperature variation on day 2, with levels returning to baseline by day 30. A spaghetti plot of individual horse skin temperatures alongside ambient air temperature over the study period provides additional context for these findings (Figure 1). The plot shows a pattern of minor skin temperature changes after treatment, characterized by an initial rise, a subsequent peak on day 1, and a gradual return to baseline by day 30. These changes appeared to correspond with ambient air temperature, with individual variability in the magnitude of the response. To evaluate changes in joint circumference, measurements were collected at pretreatment (day –14 and day –0) and posttreatment time points (days 1, 2, 3, 7, 14, and 30). Normality of the data was assessed with the Shapiro-Wilk test, confirming that all datasets followed a normal distribution (P > .05). Paired t tests were conducted to compare joint circumferences at each time point against the baseline (day –0), with no statistically significant differences observed (P > .05). Across all time points, the mean differences in joint circumference relative to baseline (day –0) ranged from –0.45 to 0.40 cm, with SDs between 0.55 and 1.07 cm. These variations as shown in Supplementary Table S6 remained within the range of measurement variability and were not statistically significant. Box plots (Figure 2) illustrate overlapping distributions of joint circumference values, further supporting the stability of joint circumferences throughout the study period.
Spaghetti plot of ambient air temperature and skin temperature (°C) at the level of the metacarpophalangeal joint (MCPJ) for 10 healthy horses before and after a single intra-articular injection of 1 mL of 2.5% polyacrylamide hydrogel and 1 mL of betamethasone sodium phosphate and betamethasone acetate esters (6 mg/mL) in their right MCPJs on day 0. The study was conducted between August 1 and September 14, 2023.
Citation: Journal of the American Veterinary Medical Association 2025; 10.2460/javma.24.10.0651
Box plot illustrating the variation in joint circumference (cm) at the level of the MCPJ over time from baseline (day –0) before and after injection as described in Figure 1. The box plot includes data from pretreatment (day –14 and day –0) and posttreatment (days 1, 2, 3, 7, 14, and 30) periods. The box represents the IQR, with the median (solid line) and mean (dashed line) indicated. Whiskers extend to values within 1.5 X IQR, and outliers are shown as dots. The data demonstrate stability in joint circumference, with no significant differences observed across time points. The study was conducted between August 1 and September 14, 2023.
Citation: Journal of the American Veterinary Medical Association 2025; 10.2460/javma.24.10.0651
Caretaker observation diaries
The COD assessments consistently showed no deviations from baseline values across all horses at any time. Comfort levels, evaluated both at rest and during walking, remained stable, with all responses indicating “0 / No Pain” from days 0 to 30. No local reactions, such as swelling or heat at the injection site (right fetlock), were reported by caretakers at any time. These daily checks provided additional assurance and credibility, confirming that no issues were observed between clinical assessments by the treating veterinarian (BW). Quality-of-life ratings, assessed daily, were consistently described as “very good” for all horses throughout the study period at all time points. Furthermore, no AEs were documented by caretakers at any time.
Discussion
This open-label safety study evaluated the concurrent IA administration of 2.5% iPAAG and BME in healthy, sound horses, demonstrating that this combination is both safe and well tolerated in MCPJs. As the first investigation into the concurrent use of these 2 treatments, this study extended prior findings on their individual use, showing that the combination can be safely administered without AEs in this study population. This study used a convenience sample of 10 horses, consistent with safety evaluations in veterinary medicine. This sample size allowed for the detection of common AEs and the establishment of an initial safety profile for the combination treatment. However, as a preliminary study, it was not designed to detect rare AEs or subtle statistical differences, nor did it include long-term follow-up to assess chronic effects. The combination of 2.5% iPAAG and BME was chosen for its potential complementary effects in a multimodal approach. The BME provides immediate and sustained anti-inflammatory action by inhibiting key inflammatory mediators,9,17,20,30,31 while 2.5% iPAAG is currently described to enhance joint capsule elasticity and modulate macrophage activity to restore joint homeostasis after a 2-week integration into the synovium.21,23–28 Over the 30-day observation period, veterinary data, including physical examinations, joint-specific clinical assessments, soundness examinations, and AE monitoring, consistently demonstrated stable clinical parameters. All horses exhibited normal vital signs, gait, and flexion tests, with no evidence of significant change in joint effusion or other abnormalities. Skin temperature measurements showed transient variations, with statistically significant increases on days 2, 3, 7, and 14 that returned to baseline by day 30. Adjustments for ambient temperature showed that the changes in skin temperature correlated with fluctuations in ambient temperature. Importantly, no clinical changes were noted in the physical examination by the treating veterinarian (BW). The scatterplot (Figure 1) analysis of temperature recordings underscored the transient nature of these changes and their correlation with environmental factors. The CODs provided additional corroboration, reporting no signs of discomfort at a rest or walk, pain, swelling, palpable heat at the injection site, or other AEs. However, the emphasis remains on the comprehensive veterinary evaluations, which provide the most robust evidence for the safety and tolerability of this combination therapy. With no AEs reported on either the CRFs or CODs, these results aligned with existing literature on the individual use of 2.5% iPAAG and BME, both of which demonstrate a low rate of AEs.5,17,21,23–28,31 This study provided preliminary evidence suggesting that the concurrent use of these treatments does not increase the risk of AEs or introduce any new potential AEs with the combination therapy. However, given the 2% to 7% incident rate of sepsis after equine joint injection, the concurrent use could limit the number of joint injections needed and therefore reduce risk of AEs associated in general with arthrocentesis.40–42
Several limitations must be acknowledged. The small sample size, while appropriate for detecting common AEs, limits the generalizability of the findings and precludes the detection of rare events. Additionally, the study was conducted exclusively in healthy horses over a 30-day period, leaving questions about its applicability to horses with OA or other joint conditions and the long-term safety of the combination therapy. The study also did not evaluate efficacy of treatment, instead focusing solely on safety and tolerability. Furthermore, recent concerns in the field suggest that corticosteroids could interfere with the macrophage-mediated mechanism of action of 2.5% iPAAG, potentially altering its long-term benefits. This possibility was not explored in our study, highlighting a need for further investigation into the molecular and histological outcomes of combining these treatments.
Future research should focus on evaluating the efficacy of this combination therapy in managing OA and other joint diseases. Larger-scale studies with longer follow-up periods are essential to confirm the long-term safety and therapeutic benefits. Investigations into the molecular mechanisms underlying the observed clinical outcomes could provide valuable insights into the synergy between 2.5% iPAAG and BME.
The concurrent IA administration of 2.5% iPAAG and BME was shown to be safe and well tolerated in the right MCPJs of healthy horses over a 30-day observation period, with no AEs or significant deviations from baseline clinical parameters. These findings provided preliminary evidence supporting the use of this combination therapy in equine veterinary practice, pending further research to establish its efficacy and long-term safety in horses with OA.
Supplementary Materials
Supplementary materials are posted online at the journal website: avmajournals.avma.org.
Acknowledgments
None reported.
Disclosures
This study received funding from Contura Vet Ltd, which is the market authorization holder for 2.5% polyacrylamide hydrogel (ArthramidVet) in the US. The funder had the following involvement with the study: provision of investigatory products and payment of costs associated. The authors have provided the following statement: “I, Megan M. Green, hereby disclose potential conflicts of interest related to the research presented in this article. I am employed by Contura Vet, the organization that sponsored and funded this research project. My employment with Contura Vet (USA) Inc may be perceived as a conflict of interest, as it could potentially influence the interpretation and reports of the study results; however, as an author, I was not involved in the data collection or data analysis. To further address this potential bias, I would like to clarify that my primary obligation as a scientist and veterinarian is to uphold the highest standards of research integrity while contributing to the advancement of knowledge in an impartial manner. If there are any questions or concerns about potential conflict of interest or the study’s integrity, please feel free to contact me directly at megan.green@conturavet.com.” All other authors declare no competing interests.
No AI-assisted technologies were used in the generation of this manuscript
Funding
Funding for the study was provided by Contura Vet Ltd.
ORCID
J. A. Barnhard https://orcid.org/0000-0002-5486-8660
References
- 1.↑
Raker CW, Baker RH, Wheat JD. Pathophysiology of equine degenerative joint disease and lameness. Proc Am Assoc Equine Pract. 1966;12:229-241.
- 2.↑
McIlwraith CW. General pathobiology of the joint and response to injury. In: McIlwraith CW, Trotter GW, eds. Joint Disease in the Horse. WB Saunders; 1996:40-70.
- 3.↑
Schlueter AE, Orth MW. Equine osteoarthritis: a brief review of the disease and its causes. Equine Comp Exerc Physiol. 2004;1:221-231. doi:10.1079/ECP200428
- 4.
Frisbie DD. Synovial joint biology and pathology. In: Equine Surgery. 3rd ed. Elsevier; 2006:1036-1054.
- 5.↑
McIlwraith CW. The use of intra-articular corticosteroids in the horse: what is known on a scientific basis? Equine Vet J. 2010;42(6):563-571. doi:10.1111/j.2042-3306.2010.00095
- 6.
van Weeren PR, de Grauw JC. Pain in osteoarthritis. Vet Clin North Am Equine Pract. 2010;26(3):619-642. doi:10.1016/j.cveq.2010.07.007
- 7.
Frisbie DD. Synovial joint biology and pathobiology. In: Auer JA, Stick JA, eds. Equine Surgery. 4th ed. WB Saunders; 2012:1096-1114.
- 8.↑
McIlwraith CW, Frisbie DD, Kawcak CE. The horse as a model of naturally occurring osteoarthritis. Bone Joint Res. 2012;1(11):297-309. doi:10.1302/2046-3758.111.2000132
- 9.↑
McIlwraith CW, Lattermann C. Intra-articular corticosteroids for knee pain—what have we learned from the equine athlete and current best practice. J Knee Surg. 2019;32(1):9-25. doi:10.1055/s-0038-1676449
- 10.
Norrdin RW, Kawcak CE, Capwell BA, McIlwraith CW. Subchondral bone failure in an equine model of overload arthrosis. Bone. 1998;22(2):133-139. doi:10.1016/s8756-3282(97)00253-6
- 11.
Hill WT. On-the-track catastrophe in the Thoroughbred racehorse. In: Ross MW, Dyson S, eds. Diagnosis and Management of Lameness in the Horse. 2nd ed. Elsevier; 2011:960-968.
- 12.
Menarim BC, Vasconcelos Machado VM, Cisneros Alvarez LE, Carneiro R, Busch L, Vulcano LC. Radiographic abnormalities in barrel racing horses with lameness referable to the metacarpophalangeal joint. J Equine Vet Sci. 2012;32:216-221. doi:10.1016/j.jevs.2011.09.064
- 13.↑
Mora-Carreño M, Briones R, Galecio J, et al. Main musculoskeletal injuries associated with lameness in Chilean rodeo horses. Arch Med Vet. 2014;46:419-424. doi:10.4067/S0301-732X2014000300011
- 14.↑
Frisbie DD. Future directions in treatment of joint disease in horses. Vet Clin North Am Equine Pract. 2005;21(3):713-724. doi:10.1016/j.cveq.2005.07.001
- 15.↑
Trotter GW. Intra-articular corticosteroids. In: McIlwraith CW, Trotter GW, eds. Joint Disease in the Horse. WB Saunders Co; 1996:237-256.
- 16.↑
Caron JP, Genovese RL. Principles and practices of joint disease treatment. In: Ross MW, Dyson SJ, eds. Diagnosis and Management of Lameness in the Horse. Elsevier; 2003:746-764
- 17.↑
Caron JP. Intra-articular injections for joint disease in horses. Vet Clin North Am Equine Pract. 2005;21(3):559-573. doi:10.1016/j.cveq.2005.07.003
- 18.
Ferris DJ, Frisbie DD, McIlwraith CW, Kawcak CE. Current joint therapy usage in equine practice: a survey of veterinarians 2009. Equine Vet J. 2011;43(5):530-535. doi:10.1111/j.2042-3306.2010.00324.x
- 19.
de Souza MV. Osteoarthritis in horses - part 1: relationship between clinical and radiographic examination for the diagnosis. Braz Arch Biol Technol. 2016;59:e16150024. doi:10.1590/1678-4324-2016150024
- 20.↑
Zanotto GM, Frisbie DD. Current joint therapy usage in equine practice: changes in the last 10 years. Equine Vet J. 2021;54:750-756. doi:10.1111/evj.13489
- 21.↑
Lowe J, Clifford L, Julian A, Koene M. Histologic and cytologic changes in normal equine joints after injection with 2.5% injectable polyacrylamide hydrogel reveal low-level macrophage-driven foreign body response. J Am Vet Med Assoc. 2024;262(5):649-657. doi:10.2460/javma.23.10.0553
- 22.↑
Katzman SA, Cissell D, Leale D, et al. Intra-articular injection of an extended-release flavopiridol formulation represents a potential alternative to other intra-articular medications for treating equine joint disease. Am J Vet Res. 2024;85(9):ajvr.24.03.0057. doi:10.2460/ajvr.24.03.0057
- 23.↑
Janssen I, Koene M, Lischer C. Intra-articular application of polyacrylamide hydrogel as a treatment of osteoarthritis in the distal interphalangeal joint: case series with 12 horses. Pferdeilkunde. 2012;28(6):650-656.
- 24.↑
Tnibar A, Schougaard H, Camitz L, et al. An international multi-centre prospective study on the efficacy of an intraarticular polyacrylamide hydrogel in horses with osteoarthritis: a 24 months follow-up. Acta Vet Scand. 2015;57(1):20-27. doi:10.1186/s13028-015-0110-6
- 25.
Christensen L, Camitz L, Illigen KE, Hansen M, Sarvaa R, Conaghan PG. Synovial incorporation of polyacrylamide hydrogel after injection into normal and osteoarthritic animal joints. Osteoarthritis Cartilage. 2016;24(11):1999-2002. doi:10.1016/j.joca.2016.07.007
- 26.
de Clifford LT, Lowe JN, McKellar CD, Bolwell C, David F. Use of a 2.5% cross-linked polyacrylamide hydrogel in the management of joint lameness in a population of flat racing Thoroughbreds: a pilot study. J Equine Vet Sci. 2019;77:57-62. doi:10.1016/j.jevs.2019.02.012
- 27.
de Clifford LT, Lowe JN, McKellar CD, McGowan C, David F. 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 Equine Vet Sci. 2021:107:103780. doi:10.1016/j.jevs.2021.103780
- 28.↑
Tnibar A. Intra-articular 2.5% polyacrylamide hydrogel, a new concept in the medication of equine osteoarthritis: a review. J Equine Vet Sci. 2022;119:104143. doi:10.1016/j.jevs.2022.104143
- 29.↑
Bathe AP, Read RM, Briggs C. Intra-articular polyacrylamide hydrogel for the treatment of 20 horses with non-responsive osteoarthritis of the interphalangeal joints: a prospective study. Vet Comp Orthop Traumatol. 2016;29(2):A4. 43rd Annual Veterinary Orthopedic Society Conference abstract 14.
- 30.↑
Knych HK, Blea JA, Arthur RM, Overly LR, McIlwraith CW. Clearance of corticosteroids following intra-articular administration of clinical doses to racehorses. Equine Vet Educ. 2016;28:140-144. doi:10.1111/eve.12532
- 31.↑
Foland JW, McIlwraith CW, Trotter GW, Powers BE, Lamar CH. Effect of betamethasone and exercise on equine carpal joints with osteochondral fragments. Vet Surg. 1994;23(5):369-376. doi:10.1111/j.1532-950X.1994.tb00497.x
- 32.↑
BetaVet (betamethasone sodium phosphate and betamethasone acetate injectable suspension). National Library of Medicine. Revised October 2024. Accessed December 1, 2024. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=3eb6b1d3-4485-4b25-aaab-92de9b2fb322
- 33.↑
Partridge E, Adam E, Wood C, et al. Residual effects of intra-articular betamethasone and triamcinolone acetonide in an equine acute synovitis model. Equine Vet J. 2023;55(5):905-915. doi:10.1111/evj.13899
- 34.↑
Dutton H. The corticosteroid laminitis story, 1: duty of care. Equine Vet J. 2007;39(1):5-6. doi:10.2746/042516407x166792
- 35.
Bailey SR, Elliott J. The corticosteroid laminitis story, 2: science of if, when and how. Equine Vet J. 2007;39(1):7-11. doi:10.2746/042516407x166035
- 36.↑
Bathe AP. The corticosteroid laminitis story, 3: the clinician’s viewpoint. Equine Vet J. 2007;39(1):12-13. doi:10.2746/042516407x165801
- 37.↑
American Association of Equine Practitioners Horse Show Committee. Guide to Veterinary Services for Horse Shows. 7th ed. American Association of Equine Practitioners; 1999.
- 38.↑
Berryhill EH, Urbina NS, Marton S, Vernau W, Alonso FH. Validation and method comparison for a point-of-care lateral flow assay measuring equine whole blood insulin concentrations. J Vet Diagn Invest. 2023;35(2):124-131. doi:10.1177/10406387221142288
- 39.↑
R: a language and environment for statistical computing. Version 4.3.2. R Foundation for Statistical Computing; 2023. Accessed January 12, 2024. https://www.R-project.org/
- 40.↑
Krause DM, Pezzanite LM, Griffenhagen GM, Hendrickson DA. Comparison of equine synovial sepsis rate following intrasynovial injection in ambulatory versus hospital settings. Equine Vet J. 2022;54(3):523-530. doi:10.1111/evj.13485
- 41.
Gillespie CC, Adams SB, Moore GE. Methods and variables associated with the risk of septic arthritis following intra-articular injections in horses: a survey of veterinarians. Vet Surg. 2016;45(8):1071-1076. doi:10.1111/vsu.12563
- 42.↑
Steel CM, Pannirselvam RR, Anderson GA. Risk of septic arthritis after intra-articular medication: a study of 16,624 injections in Thoroughbred racehorses. Aust Vet J. 2013;91(7):268-273. doi:10.1111/avj.12073
