Intra-articular hyaluronan treatment and its mechanism of action in relieving inflammation and pain in equine arthritis : Clinical and experimental trials on treatment efficacy of hyaluronan and its effects on synovial fluid biomarkers

Intra-articular (IA) inflammation resulting in lameness is a common health problem in horses. Exogenous IA hyaluronic acid has been shown to provide an analgesic effect in equine and human osteoarthritis. High molecular weight non-animal stabilized hyaluronic acid (NASHA) has gained popularity in the treatment of human arthritic conditions due to its long-acting pain-relieving effects. In animal models, hyaluronan has been demonstrated to reduce pain by protecting nociceptive nerve endings and blocking pain receptor channels. Inflammatory and degenerative activity inside the joint can be studied in vivo by analysis of synovial fluid (SF) biomarkers. In addition to pro-inflammatory mediators, several anabolic and anti-inflammatory substances are produced during the disease process. The response of SF biomarkers after IA hyaluronan injection, alone or in combination with other substances, has been examined only in a few equine studies. Aim of the studies was to examine the efficacy of IA NASHA in relieving lameness and related signs of IA inflammation in clinical and experimental studies. We also investigated the effect of NASHA on various SF biomarkers. In addition, we explored possible adverse effects of NASHA on clinical signs of IA inflammation and SF. In the clinical study, we compared the response to treatment of lameness localized in the equine metacarpophalangeal joint injected with NASHA or placebo (saline). We also investigated the response of SF prostaglandin E2 (PGE2), substance P, aggrecan chondroitin sulphate 846 epitope (CS846), and carboxypeptide of type II collagen (CPII) concentrations to the NASHA and placebo treatments. After collection of baseline SF samples followed by IA diagnostic anaesthesia, horses in the treatment group received 3 ml of a NASHA product (20 mg/ml) intra-articularly, and those in the placebo group received an equivalent volume of sterile 0.9% saline solution. The horses were re-evaluated and a second SF sample was obtained after a two-week period. In the experimental study, the aim was to measure the SF interleukin-1 receptor antagonist (IL-1ra), platelet-derived growth factor BB (PDGF-BB), transforming growth factor beta 1 (TGF-β1), and tumour necrosis factor alpha (TNF-α) concentrations before and after surgically induced cartilage defect and sham operation as a control in horses. We also investigated whether the concentrations of selected biomarkers in SF changed following NASHA injection. Results of the clinical study indicate that a single IA NASHA injection is not better than a single saline injection for reducing lameness in horses with synovitis or mild osteoarthritis. However, IA NASHA may have some beneficial effects in modifying mild clinical signs. The decrease in the SF concentration of the cartilage-derived biomarker CS846 only in the NASHA group suggests that less damage and hence less repair to the cartilage has occurred post-injection. Creation of the cartilage defect and sham operation lead to an increase of synovial fluid IL-1ra and TNF-α concentrations in the experimental study, but NASHA failed to produce changes in SF biomarkers.The significant increase in SF white blood cell count after IA NASHA may indicate a mild inflammatory response. However, as no clinical adverse effects were observed, IA NASHA appeared to be well tolerated.

Nivelperäinen kipu ja sen aiheuttama ontuma on yleinen terveysvaiva hevosilla. Nivelensisäisen hyaluronihappohoidon on osoitettu lievittävän oireita sekä ihmisen että hevosen osteoartiitissa. Nivelen tulehdus- ja rappeutumisprosessia voidaan tutkia nivelnesteen sisältämien merkkiaineiden avulla. Näiden vastetta nivelensisäiseen hyaluronihappohoitoon on raportoitu ainoastaan muutamassa hevostutkimuksessa. Tämän tutkimuksen tavoitteena oli selvittää suurimolekyylisen ei-eläinperäisen stabiloidun hyaluronihapon (high molecular weight non-animal stabilized hyaluronic acid, NASHA) tehoa hevosen ontumaan ja muihin nivelensisäisen tulehduksen aiheuttamiin oireisiin kliinisessä kaksoissokkoutetussa lumekontrolloidussa potilastutkimuksessa ja kokeellisessa tutkimuksessa. Lisäksi tutkittiin nivelnesteen solu- ja proteiinipitoisuuden sekä valikoitujen nivelnesteen biomerkkiaineiden (PGE2, substance P, CS846, CPII, IL-1ra, PDGF-BB, TGF-β1, TNF-α) vastetta hoitoon. Tulokset osoittavat ettei NASHA nivelensisäisesti annosteltuna ole tehokkaampi kuin fysiologinen suolaliuos lyhyellä aikavälillä (kaksi viikkoa) ontuman lievittämisessä. Hoito voi kuitenkin lievittää muita nivelkivun oireita. Myöskään nivelnesteen merkkiainepitoisuudet eivät eronneet merkittävästi NASHA- ja lumehoidon tai NASHA-hoidon ja ilman hoitoa olleiden nivelten (kokeellinen tutkimus) välillä. Nivelensisäinen NASHA-hoito indusoi nivelnesteessä lievästä tulehdusreaktiosta kertovan valkosolujen nousun, joka ei kuitenkaan heijastunut kliinisiin oireisiin, eli kliinisesti nivelensisäisen NASHA-hoidon ei todettu aiheuttavan lainkaan haittavaikutuksia.

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