Title: Pain Phenotypes and their Underlying Mechanisms in Inflammatory Arthritis (PUMIA)
Funder: Department of Health and Social Care

Abstract: BackgroundInflammatory arthritis (IA) affects ~half a million people in the UK. Although joint inflammation is often well-controlled, pain frequently persists and controlling persistent pain is a significant unmet need for people living with IA. Until recently, the accepted dogma by rheumatologists was that pain occurs as the result of mediators of joint inflammation activating local pain-signalling nerve fibres in the joint. As such, pain treatment has been aimed at reducing joint inflammation. However, increasing evidence suggests that other mechanisms emerge, such as increased sensitivity of peripheral nerves to stimulation (peripheral sensitisation) and a potential important role for the central nervous system's processing of pain (central sensitisation).One way in which we might rapidly improve the treatment of pain in IA is by identifying an individual's pain type in the clinic, then tailor their pain treatment accordingly. Currently this is not routine practice and is constrained by (i) limited understanding of different pain phenotypes in IA and (ii) insufficient ability to easily measure them in the clinical setting. AimThis study aims to develop more effective and patient-centric approaches to tailor pain treatments by For the first time, using multiple methods of measuring peripheral and central pain, to generate accurate sensory profiles of patients with IA, and exploring how pain types change over disease course. Developing a robust approach to assess pain type in the clinical settingMethods1: To validate a novel assessment of peripheral pain, I will compare change in pain scores after intra-articular injection of lidocaine (and steroid) versus placebo (steroid only). 2: To test the hypothesis that peripheral pain predominates at diagnosis but over time the nature of pain changes to be caused by primarily peripheral sensitisation in some patients and to be caused by primarily central sensitisation in other patients, I will perform longitudinal detailed pain profiling. This will include measures of peripheral pain (response to intra-articular injection of lidocaine, active inflammation on joint ultrasound) and central sensitisation (painDETECT questionnaire, pain pressure thresholds, temporal summation and central pain modulation).3: To identify underlying mechanisms of pain in IA I will use detailed pain profiling, as described above, in a cross-sectional cohort of patients with established IA.4: To develop a strategy to assess pain type in clinic I will perform a qualitative study using 1:1 interview and focus groups to identify key descriptions of certain pain phenotypes Anticipated impact and disseminationThis study will address the two limitations to current provision of targeted pain treatment in IA; firstly, by providing an in depth understanding of the mechanisms underlying pain phenotypes in IA which will guide choice of targeted pain treatment and secondly by the development of a robust strategy to assess pain phenotype in the clinical setting. Targeted pain treatment has the potential to improve pain outcomes, quality of life, emotional wellbeing and work productivity for patients with IA and reduce burden on primary and secondary care services. I will disseminate my findings through publications, presentations, public engagement events and our expert patient network.

Lay abstract: Background:Inflammatory arthritis (IA), including rheumatoid arthritis, psoriatic arthritis and axial spondylarthritis, affects approximately 500,000 people in the UK. Although significant advances in treatment over the last 20 years means that most patients with IA now have very minimal joint inflammation, surprisingly the burden of pain has not significantly changed.Pain is associated with reduced quality of life, changes in social functioning and in-ability to cope with disease. As a result, controlling chronic pain has been identified by patients as a significant unmet medical need in IA.Pain can originate from the peripheral nervous system (activation of the nerves in the joint) or the central nervous system (by the brain and spinal cord's processing of pain). There is increasing evidence that both peripheral and central pain types affect certain patients with IA. Since the treatment of central vs. peripheral pain differs, it is important to identify these different pain types in the clinical setting. The problem:One way in which we might rapidly improve the treatment of pain in IA is by identifying an individual's pain type in the clinic, then tailor their pain treatment accordingly. Currently this is not routine practice because the understanding of different types of pain in IA is limited and there is no simple way to assess pain type in the clinic.Aim:This study aims to develop more effective and patient-centric approaches to tailor pain treatments by For the first time, using multiple methods of measuring peripheral and central pain, to generate accurate sensory profiles of patients with IA, and exploring how pain types change over disease course. Developing a robust approach to assess pain type in the clinical settingMethods: 1) To validate a new method of assessing peripheral pain, I will compare change in pain scores after joint injection of local anaesthetic versus placebo. 2) To identify pain types and their underlying mechanisms, I will use measures of central pain (painDETECT questionnaire, clinical pain perception tests including pain pressure threshold, temporal summation and central pain modulation) and peripheral pain (response to joint injection of local anaesthetic, active inflammation on joint ultrasound) to create a sensory profile of (i) a first group of patients with a new diagnosis of IA followed up over 2 years and in (ii) a second group of patients with longstanding IA at one time point. 3) To develop a strategy to assess pain type in clinic I will perform a qualitative study using 1:1 interview and focus groups to explore how patients with different types of pain describe their painPatient and public involvement:Patient opinion is vitally important to effectively develop research and patients have been and will continue to be actively engaged throughout this study. This study conception is a result of discussions between academics, clinicians and Expert Patients. The protocol including choice of study questionnaires and qualitative study interview schedule has been developed based on feedback from regular meetings with the expert patient group, a discussion with members of National Rheumatoid Arthritis society (NRAS) and a focus group with expert patients on their perceptions of pain. I will continue to hold regular expert patient group meetings to review study progress and one expert patient will co-lead the focus groups in my qualitative study.Dissemination:I will publish my findings in peer reviewed journals, present at scientific conferences and disseminate findings through the several academic groups involved in this study to ensure a wide but relevant range of academic and clinicians is reached.I will present my research at patient and public engagement events and through the NRAS newsletter and expert patient blog.

Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES;7.1 INDIVIDUAL CARE NEEDS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM