Osteoarthritis (OA) is the most prevalent form of arthritis in Australia and worldwide. OA is a chronic and painful disease of the synovial joint, and a leading cause of disability. Knees, hips and hands are the most commonly affected joints. Pain is the most prominent symptom which drives patients to seek healthcare. Thus, OA represents an enormous health and economic burden on patients and societies. There were 100,000 knee and hip replacement procedures (mainly due to OA) performed in Australian hospitals during 2015, with a cost of $2 billion a year. Despite this, there are no proven strategies to prevent, slow, halt or reverse the OA progression. Current OA management is mostly palliative and focuses on pain relief. ‘First-line’ agents, such as paracetamol and non-steroid anti-inflammatory drugs (NSAIDs), have only small to moderate efficacy, with >75% of patients reporting the need for additional symptomatic treatment. Therefore, pain control remains a substantial unmet need for OA treatment. In addition to the need to develop drugs that can slow disease progression, there is a critical need to develop more effective pain relief agents for OA patients.
Current ‘one size fits all’ approach in OA management and ongoing clinical trials and lack of in-depth understanding of the mechanisms of OA structural damage and pain explain the overall lack of treatment efficacy and frequent negative findings from OA clinical trials. OA is a heterogeneous condition characterised by a complex and multifactorial nature. With the increasing understanding of OA risk factors and pathological processes, it has become clear that OA is not only a disease of cartilage but it can be divided into different clinical phenotypes (e.g. chronic pain-, inflammatory-, bone- phenotypes). This leads to a large variation in clinical presentations (pain) and responses to OA treatment. Therefore, in order to optimise treatment effects in OA, the ‘one size fits all’ treatment approach needs to change to more tailored interventions targeting specific subgroups/phenotypes.
My research primarily focuses on the identification of biomechanical risk factors for chronic pain and OA, identifying OA pain subgroups/phenotypes and testing new therapeutic strategies based on phenotyping. I have identified distinct OA pain subgroups using advanced statistical methods. These subgroups differ in the underlying causes and mechanisms and consequently may require different therapeutic approaches. My research findings have contributed to a paradigm shift in the understanding of the pathogenesis of OA and OA-related pain.
Pain experience in knee OA is individualised and complex. Inflammatory and metabolic pathways have been suggested to play a key role in the pathophysiology of osteoarthritis-related pain. Our recent studies demonstrate that pain in OA consists of homogeneous subgroups following distinct pain trajectories. Pilot data from a small sample found that inflammatory markers may be involved in the development and maintenance of worse pain trajectories. This project will expand our biomarker testing to a larger sample to determine the role of inflammatory and metabolic mechanisms in the development and maintenance of different pain presentations. This study will facilitate a comprehensive understanding of Inflammatory and metabolic mechanism in OA pain patterns, and , will also identify biomarkers that can define optimal patient populations for specific interventions, and have the potential to develop new therapeutic targets.
Multisite musculoskeletal pain (MSMP) is a common pain presentation. Musculoskeletal pain often occurs at multiple anatomical sites simultaneously with an estimate of 75% of adults aged ≥65 years having pain at multiple sites. Multisite musculoskeletal pain (MSMP) has a worse prognosis and a more detrimental impact on health outcomes than single-site pain. Experiencing MSMP is associated with poorer physical and mental health, poorer sleep quality, and increased risk of falls, and fractures, suggesting that MSMP could be a distinct disease entity.
Lipidomic profiling (including 850 lipid species) was performed in 536 participants from Tasmanian Older Adult Cohort Study (TASOAC) with assessments at baseline, 2.6-, 5.1- and 10.7-year. MSMP was measured by a self-reported pain questionnaire at four time-points and defined as painful sites ≥4; while serum samples for lipidomic profiling were only collected at the 2.6-year follow-up. Lipid concentrations were natural log-transformed. Persistent MSMP was defined if participants had MSMP at 2.6-, 5.1- and 10.7-year. The Benjamini Hochberg method was used for controlling for multiple testing. Among 536 serum samples, 530 passed quality control. Of these, there were 112 (21%) and 418 (79%) participants having persistent and non-persistent MSMP, respectively. Participants having persistent MSMP had a lower level of monohexosylceramide (HexCer) (d18:1/24:0 and d18:1/22:0), lysophosphatidylcholine (LPC) (18:2 [sn2], 18:1 [sn1]), and 15-MHDA [sn1] [104_sn1]) than those with non-persistent MSMP. In multivariable analysis with adjustment for age, sex, body mass index, physical activity, diabetes, total cholesterol, HexCer (d18:1/24:0 and d18:1/22:0), and LPC (18:2 [sn2], 18:1 [sn1]), and 15-MHDA [sn1] [104_sn1]) were significantly associated with persistent MSMP (OR ranging from 0.22 to 0.33, per log pmol/ml increase, p≤1.94×10-3) after controlling for multiple testing.
We are now examining the associations of lipids with other pain presentations such as pain trajectories, pain severity etc.
This research project will address an unmet clinical need for optimal pain management for patients with pain. OA is the most common form of arthritis and is the leading cause of pain and disability. With the growing aging population, along with the increase in obesity, OA has become a huge societal and economic burden in the developed world. Despite this, there are no effective disease-modifying OA drugs and the existing pain therapies have limited efficacy and a substantial risk of adverse events. OA pain is highly heterogeneous, with pain presentations varying among patients. Therefore, it is not surprising to see far disappointing results from “one-size fits all” treatment approaches in OA pain patients. Our research will directly address this need by identifying pain subgroups and providing an optimal patient selection tool. By using metabolomics to determine underlying mechanisms of different pain subgroups, we will also identify biomarkers that can define optimal patient populations for specific interventions, and have the potential to develop new therapeutic targets. This project will fundamentally change clinical pain management in patients with OA by selecting the right patients for the right treatment. This has significant benefits for families and communities to improve OA patients’ quality of life and save substantial healthcare costs in Australia and worldwide.
Our research will benefit all patients with OA pain, by addressing the heterogeneity of OA pain and its mechanisms. One of the most pressing needs in the health field is to select the right treatments for the right patients. This is a more pressing issue in the OA field, given the lack of effective disease-modifying OA drugs and limited efficacy of analgesics. A significant advance on improving the efficacy of current OA pain treatments would be a stratification method that can select patients who are most likely to respond to the treatments and minimise their suffering related to ineffective treatments. Based on our previously defined OA pain subgroups which differ in metabolic abnormalities and central pain processing, have different clinical health outcomes, and show a degree of phenotypic stability over time, this suggests that these pain subgroups are clinically useful in OA patients’ stratification. Researching metabolic mechanisms using metabolomics will better predict who will or will not benefit from a treatment, and who will or will not have the highest efficacy and the lowest safety concerns to a given treatment. Furthermore, the nature of cohort studies included in this project will enable the identification of mechanisms that underlie transition to and maintenance of OA pain. Therefore, this work will lead to a paradigm shift in our understanding of OA pain, and will lay the foundation for targeted treatments for patients with OA pain as well as other common and complex chronic pain conditions with similar pain mechanisms involved.
The outcomes of this project will advance scientific knowledge in revealing mechanisms of OA pain heterogeneity, and significantly improve the methods for stratifying OA pain patients. The project is multidisciplinary. It will provide new insights into OA pain mechanisms and treatments that will assist with developing an optimal and tailored therapeutic strategy for a selected subgroup of OA patients. Therefore, passing on the knowledge to other researchers, clinicians, and the wider community through communicating and disseminating our research findings is an important part of our research plan. We will publish the results of our research in top-tier journals and use high quality national and international pain and rheumatology conferences as a key part of the scientific communication chain. While data arising from our research lead to high impact and significant findings in academia, new biomarkers identified from this project may advance developing therapeutic products for Australia’s pharmaceutical industry to benefit more patients who are living with pain.