Knee osteoarthritis is a leading cause of pain and disability and frequently results in total knee arthroplasty (TKA). Decisions about surgery and postoperative management rely largely on subjective pain scales and patient-reported outcome measures (PROMs), and 10–15% of patients remain dissatisfied after TKA despite technically successful surgery. Evidence suggests that pain is partly reflected in peripheral immune signalling, yet this neuroimmune interface has not been studied in patients with joint pain due to knee osteoarthritis. This study will explore whether peripheral immune responses (interleukin-1 beta, IL-1β) are associated with pain and may serve as objective pain biomarkers in patients with painful knee osteoarthritis compared with pain-free controls and how these markers relate to pain and psychological (anxiety, depression and pain catastrophising) PROMs. This will be the first study to correlate pain markers (peripheral immune responses) with subjective pain levels in orthopaedic patients with symptomatic knee osteoarthritis.

This is a protocol for a prospective cross-sectional matched-subject observational study. We will include 20 adults undergoing unilateral primary TKA for painful advanced knee osteoarthritis, their contralateral pain-free knees as internal controls and 20 age and sex matched healthy controls without joint pain or functional limitation. All participants will undergo standardised clinical assessment and complete pain and psychological PROMs. In patients with TKA, venous blood will be collected pre-operatively. During TKA surgery, synovial fluid will be aspirated from the painful operated knee and the contralateral pain-free knee. Healthy controls will provide a single venous blood sample at a hospital visit. Peripheral blood mononuclear cells and synovial fluid mononuclear cells will be stimulated ex vivo with toll-like receptor 2 and 4 agonists to quantify IL-1β release. In parallel, hyperspectral imaging will characterise unstimulated immune cell phenotypes. Multivariable statistical and machine-learning approaches will relate biomarker profiles to pain and psychological PROMs.

The study has been approved by the Southern Adelaide Local Health Network (SALHN) HREC (references: 2024/HRE00253, SSA 2024/SSA00641). Written informed consent will be obtained from all participants. Study results will be disseminated through peer-reviewed publications and presentations at national and international scientific conferences.

ACTRN12626000084381.

Recovery after extremity fracture is influenced by injury-related impairments, functional capacity, symptom severity and psychosocial well-being, emphasising the need for patient-reported outcome measures (PROMs). Despite increasing adoption of Patient-Reported Outcomes Measurement Information System (PROMIS) and legacy PROMs in orthopaedic research, substantial knowledge gaps remain regarding their measurement properties, comparability and clinical utility, particularly in fracture populations. Our aim is to develop meaningful guidance to clinicians regarding the use of PROMs in treating orthopaedic fracture patients.

A prospective cohort of 1500 patients across 14 centres presenting with isolated extremity fractures being treated operatively or non-operatively will be recruited prospectively. We will aim to recruit 300 patients for each of five fracture types: isolated hip, tibial shaft, ankle/pilon, proximal humerus and distal radius fracture. All procedures and management will be performed according to the site’s standard of care and treatment protocol. For patients treated non-operatively, the index visit (first study assessment) will be performed at the first orthopaedic treatment encounter (eg, emergency department visit or outpatient fracture clinic). Surgically treated patients will have PROMs collected anytime from the day of the surgery up to discharge from hospital for the index visit. Follow-up visits will be performed at 2–3 weeks, 6–8 weeks, 10–13 weeks, 6 months and 1 year after the index visit. At baseline, we will document injury data, demographic and sociodemographic data, and radiographic classification using the AO classification system. Patient-perceived functioning will be assessed with PROMIS Physical Function (PF), PROMIS Upper Extremity, PROMIS Global Health, Knee and Injury Osteoarthritis Outcome Score-12, Hip Disability and Osteoarthritis Outcome Score-12, Foot and Ankle Ability Measure and Quick Disabilities of the Arm, Shoulder and Hand. The following domains and PROMs will also be captured: symptoms of anxiety and depression (PROMIS Anxiety; PROMIS Depression), patient activation (Patient Activation Measures (PAM)-10) and a patient’s ability to fulfil social roles (PROMIS Social Roles).

The range and normative limits of the PROMs collected will be defined using standard descriptive statistics. We will crosswalk or validate PROMIS measures with legacy instruments for PF using an Item Response Theory (IRT)-based linking model and compare it to non-IRT models (such as equipercentile linking). Lastly, we will assess the PROM-based recovery trajectory after fracture, overall and after adjusting for relevant demographic, clinical or biopsychosocial factors.

Ethics approval for this study was granted from the local Ethics Committees or Institutional Review Board at each of the participating sites prior to patient enrolment. Austin: Institutional Review Board University of Texas at Austin, STUDY00000262; Boston: Mass General Brigham, 2019P000397; Los Angeles: Cedars-Sinai, Office of Research Compliance and Quality Improvement, STUDY00000081; Miami: University of Miami Human Subject Research Office, 20221353; Bogotá: Comité Corporativo de Ética en Investigación, CCEI-15607-2023; Berlin: GoFitFast: under Homburg approval; Recovery/Linking: Ethikkommission Charité Universitätsmedizin Berlin, EA2/026/21; Homburg: GoFitFast: Ethikkommission der Ärztekammer des Saarlandes, 232/19; Recovery/Linking: under Charité approval; Murnau: under umbrella from Homburg and Charité, GoFitFast: under Homburg approval, Recovery/Linking: under Charité approval; Tübingen: GoFitFast: Ethik-Kommission, Universitätsklinikum Tübingen, 393/2022BO2; Freiburg: Ethik-Kommission Albert-Ludwigs-Universität Freiburg, 21–1401; Rostock: Ethikkommission an der Universitätsmedizin Rostock, A 2024–0113; Innsbruck: Ethikkommission der Medizinischen Universität Innsbruck, 1258/2021; Oxford: HRA and Health and Care Research Wales, 20/EE/0051; London: HRA and Health and Care Research Wales, 20/EE/0051; Groningen: Medical Ethics Review Board University Medical Center Groningen, METc 2023/187 16882; Non-WMO waiver; Zwolle: Medical Ethics Review Board University Medical Center Groningen, METc 2023/187 16882; Non-WMO waiver. The results of this study will be published in peer-reviewed journals and presented at different conferences.

NCT04113044