Technology

Diagnosis and treatment of Osteoarthritis

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Through thorough research on horses joint’s, ARTROA has discovered biomarkers (neo-epitopes) that releases once an inflammation starts in the cartilage and underlying bone. The biomarkers are measured through a sample of synovial fluid, serum or saliva and gives an indication of how severe the joint destruction is and which of the joint structure that is involved (cartilage or bone or both).

Schematic drawing illustrating the established interdisciplinary collaboration between SLU, GU, Sahlgrenska University Hospital and Chalmers. The overall aim is to decipher the mechanisms underlying the initiation of osteoarthritis, a process that is conserved between man and horse, disentangle the progression of the disease, and elucidate new strategies for diagnosis and pharmacological intervention.

A schematic representation of the longitudinal development of OA.

Osteoarthritis disease progression extend over days to years. The disease starts in the cells in the cartilage, bone or and the synovial membrane. Cellular parameters are changed and the cells produce pain- and inflammatory substances.The biochemical degradation initiated by inflammation in the early event is not possible to determine with today’s diagnostic methods when the processes in the cartilage and bone is still reversible. When the horse becomes clinically lame the progression of the disease has advanced and becomes more and more irreversible.

The different imaging techniques available today can only evaluate the irreversible morphological changes and not the early catabolic biochemical processes. COMP fragmentation in articular cartilage is an early response to inflammation, we have discovered a neo-epitope of COMP that is released in acute and early stages of osteoarthritis. Additional the fragmentation of biglycan is an early response of the inflammation in the subchondral bone. We have discovered a neo-epitope of biglycan that is released in the early stages of bone sclerosis.

Precision diagnosis and a novel treatment for osteoarthritis in horses

Osteoarthritis (OA) is a chronic low-grade inflammatory disease, with subtle progression, including tissue destruction before clinical gait asymmetries become apparent. The need to prevent, diagnose and treat OA, while the disease is still reversible, relies on early detection of molecular changes (biomarkers) before the onset of chronic OA. The present costly imaging techniques (radiographs, MR, CT) can only detect late structural changes. Gait asymmetries and clinical lameness are detected when OA progresses from reversible to the irreversible stage.

Regulatory bodies, European Medicines Agency, Food and Drug Administration and OA international research organizations, all recognize the importance of biomarkers, since early identification using biomarkers allow for timely, targeted disease modifying osteoarthritic drugs (DMOAD), potentially preventing joint pain and irreversible damage. We have identified novel soluble neo-epitopes reflecting ongoing extracellular matrix degradation in osteoarthritic cartilage and bone that can be quantified in body fluids (synovial fluid, blood, saliva). Development of validated customized ELISAs for detecting superficial cartilage damage (COMP156) and bone changes (BGN262), as well as deeper cartilage degradation (COMP644) in OA has been achieved. These biomarkers can monitor destruction of articular cartilage and subchondral bone during training programs (prevention), diagnose and post-intervention (treatment efficacy and side effect) and during rehabilitation (post-treatment). Using these biomarkers for diagnosis also enables an understanding of molecular mechanisms (endotypes) and distinguishing progressive from non-progressive cases. The biomarkers can identify bone-driven and cartilage-driven endotypes. Defining the specific endotypes, helps categorise the horses into biomarker assisted sub-groups for tailored treatments, improving clinical trial outcome. Monitoring the levels of the different biomarkers can aid in evaluating the efficacy of treatment and the effect of different rehabilitation regimes.

Currently registered pharmacological OA treatments only improve pain/symptoms and are frequently associated with side effects. There are no approved DMOADs on the market. A DMOAD must show improvement in joint structure, and slow down the progression of tissue destruction of cartilage and bone, with or without an efficacy on joint pain. A new drug that fulfill these criteria has been developed by the group and together with the biomarker have been validated in a double-blind randomised clinical trial in racehorses. The introduction of the drug on the market in Sweden has improved OA treatment by promoting joint tissue healing, slowing disease progression and elimination of joint pain without causing side effects. The biomarkers are in use for measuring the efficacy and/or side-effects after treatment.

References:

1) Salivary biglycan-neo-epitope-BGN262: A novel surrogate biomarker for equine osteoarthritic sub-chondral bone sclerosis and to monitor the effect of short-term training and surface arena. Adepu S, Lord M, Hugoh Z, Nyström S, Mattsson-Hulten L, Abrahamsson-Aurell K,Lützelschwab C, Skiöldebrand E. Osteoarthritis and Cartilage Open 5 (2023) 100354

2) Biglycan Neo-epitope (BGN262),a Novel biomarker for screening early changes in equine osteoarthritic subchondral bone. Adepu S, Ekman S, Leth J, Johansson U, Lindaahl A, Skiöldebrand E. Osteoarthritis Cartilage. 2022 Oct; 30(10):1328-1336.

3) A randomized, triple-blinded controlled clinical study with a novel disease-modifying drug combination in equine lameness-associated osteoarthritis. Skiöldebrand E, Adepu S, Lützelschwab C, Nyström S, Lindahl A, Abrahamsson-Aurell K, Hansson E. Osteoarthritis and Cartilage Open. 2023 Jun 16;5(3):100381.

4) Effect of circadian rhythm, age, training, and acute lameness on serum concentrations of cartilage oligomeric matrix protein (COMP) neo-epitope in horses. Stina Ekman, Anders Lindahl, Ulla Rüetschi, Anna Jansson, Kristina Björkman, Kristin Abrahamsson – Aurell, Sigríður Björnsdóttir, Maria Löfgren, Lillemor Mattsson Hultén and Eva Skiöldebrand. Equine Vet J. 2019 Sep;51(5):674-680. doi: 10.1111/evj.13082. Epub 2019 Mar 6.

5) Cartilage oligomeric matrix protein neoepitope in the synovial fluid of horses with acute lameness: A new biomarker for the early stages of osteoarthritis. Skiöldebrand E, Ekman S, Mattsson Hultén L, Svala E, Björkman K, Lindahl A, Lundqvist A, Önnerfjord P, Sihlbom C, Rüetschi U. Equine Vet J. 2017 Sep;49(5):662-667.

6) An inflammatory equine model demonstrates dynamic changes of immune response and cartilage matrix molecule degradation in vitro. Svala E, Löfgren M, Sihlbom C, Rüetschi U, Lindahl A, Ekman S, Skiöldebrand E. Connect Tissue Res. 2015;56(4):315-25.

7) A novel treatment combination of sildenafil, mepivacaine, and glucose with disease modifying properties, in a pony with lameness associated osteoarthritis – a case report. Skiöldebrand E, Abrahamsson Aurell K, Adepu S, Lindahl A, Hansson E. J Clin Case Reports, 2023, Volume 13:06.