One year in review: ultrasound in arthritis

Musculoskeletal ultrasound (MSUS) has become a relevant part of rheumatology practice and research because it substantially allows us to optimize management of rheumatic and musculoskeletal diseases. This non-invasive imaging modality is a valuable point-of-care tool to accurately evaluate intra-articular and periarticular structures involved in a wide range of rheumatic diseases in adults and children. In addition, MSUS is an invaluable bedside aid for guiding accurate and safe musculoskeletal aspirations, injections and biopsies. This review provides an overview of the literature of the last year on the role of MSUS in arthritis

A review of arthritis diagnosis techniques in artificial intelligence era: Current trends and research challenges

Deep learning, a branch of artificial intelligence, has achieved unprecedented performance in several domains including medicine to assist with efficient diagnosis of diseases, prediction of disease progression and pre-screening step for physicians. Due to its significant breakthroughs, deep learning is now being used for the diagnosis of arthritis, which is a chronic disease affecting young to aged population. This paper provides a survey of recent and the most representative deep learning techniques (published between 2018 to 2020) for the diagnosis of osteoarthritis and rheumatoid arthritis. The paper also reviews traditional machine learning methods (published 2015 onward) and their application for the diagnosis of these diseases. The paper identifies open problems and research gaps. We believe that deep learning can assist general practitioners and consultants to predict the course of the disease, make treatment propositions and appraise their potential benefits

Ultrasound imaging in joint and soft tissue inflammation

The use of ultrasound as an extended and more objective investigation performed as an extension of physical examination has a potential role in studying inflammation in different rheumatic diseases such as rheumatoid arthritis (RT) and spondylarthropathy (SpA). Rheumatoid arthritis is a chronic disease causing joint inflammation and destruction. Metacarpophalangeal (MCP) joint involvement is one of the earliest and most permanent signs of RA. US has been used to detect synovitis and erosions in MCP joints with high accuracy when compared to X-ray and magnetic resonance imaging (MRI). In RA joints, power Doppler has been used to detect increased blood flow as a potential sign of inflammation but grey-scale and power Doppler ultrasonography was not compared to another method to detect increased blood flow in MCP joints. After RA the next most common inflammatory group of diseases are the seronegative spondylarthropathies. In SpA joint inflammation and ankylosis occur in addition to periarticular enthesitis, which is one of the major hallmarks of the disease and has been poorly studied by ultrasonography. In order to reduce observer variation in musculoskeletal ultrasound examination to the level of other imaging methods it is necessary to avoid direct contact between the observer and the subject. This problem has been addressed in the aerospace industry and led to the development of air-coupled non-destructive testing. Air-coupled ultrasonography has the potential in medial imaging to exclude observer variation if it is able to depict human anatomy. There are currently no data regarding airborne ultrasound in the musculoskeletal ultrasound literature

The role of ultrasonography in the investigation and management of rheumatic conditions

Aims: The importance of inflammation in the development of joint damage and subsequent functional limitation, together with the increasing awareness that clinical assessment is insensitive at detecting synovitis, has led to the use of modern imaging modalities such as ultrasonography (US) in rheumatology. This with an emphasis on improved detection of synovitis and earlier, more effective therapeutic intervention. The aim of this thesis was to investigate the role of US in routine practice, by validating its role in diagnosis, prognosis and therapeutic intervention, across a range ofcommon rheumatological clinical scenarios. Methods: Construct validity for US-detected synovitis in knee arthritides was examined by comparison with clinical assessment and arthroscopy. In order to examine the benefits of US-guided joint injections, the accuracy of guided shoulder injections was observed. As well, the efficacy of US-guided corticosteroid injections in hip osteoarthritis and predictors of outcome were also assessed. The sensitivity of US over clinical examination was assessed in a cohort of rheumatoid arthritis patients with low disease activity levels. The diagnostic and therapeutic predictive value of US-detected synovitis in inflammatory hand pain was examined in a large cohort. Finally the clinical utility of US at altering diagnosis and management in clinical rheumatology practice was prospectively examined. Results: For detection of knee synovitis, using arthroscopy as the gold-standard, US had higher sensitivity (98 vs 85%) and specificity (75 vs 25%) than clinical assessment. Kappa values for inter- and intra-reader reliability of US were 0.71 and 0.85 respectively. In the shoulder US-guided injections were 100% accurate, but 55% had evidence of extrabursal contrast limited to the tissue planes adjacent to the bursa. Outcome following hip injection was poor, but synovitis without osteophytes on US was the best predictor of short term benefit. In rheumatoid arthritis patients in clinical remission, the majority satisfying established remission criteria, US detected gray-scale and power Doppler (PD) synovitis in 85% and 60% patients respectively. The kappa value for inter-reader reliability was 0.60 for gray-scale, and intra-reader reliability was 0:60 for gray-scale and 0.62 for PD.Most inflammatory hand pain patients without clinical evidence of an inflammatory arthritis had US synovitis (55%); and US (p<O.OOl), but not clinical, synovitis was significantly associated with response to parenteral corticosteroid therapy. The site-specific diagnosis (53%) and management (53%) was altered in most patients referred for US in a routine clinic. Conclusion: Ultrasonography is now well validated in synovitis detection in small and large joints, and this has substantial implications for the accurate and early diagnosis of inflammatory arthritis, as well as in monitoring outcomes to therapy in rheumatoid arthritis. Ultrasonography can aid prognosis as well as improving placement of guided intra-articular therapies. This work has demonstrated that US has a significant role to play in rheumatology practice

In Vivo Fluorescence Imaging of E-Selectin: Quantitative Detection of Endothelial Activation in Arthritis

Rheumatoid arthritis (RA) is a chronic progressive systemic inflammatory disease, characterized by synovial inflammation and localized destruction of cartilage and bone. Heterogeneity in the clinical presentation of RA and uncertainty about which patients will respond to treatment makes diagnosis and management challenging. Fluorescent imaging in the near infrared (NIR) spectrum significantly decreases tissue autofluorescence offering unique potential to detect specific molecular targets in vivo. E-selectin or endothelial adhesion molecule-1 (ELAM-1), a 115kDa glycoprotein induced on endothelial cells in response to pro-inflammatory cytokines involved in RA, such as interleukin (IL)-1 beta and tumour necrosis factor alpha (TNF alpha). E-selectin has been well validated as a potential biomarker of disease activity. My study aimed to investigate whether E-selectin targeted optical imaging in vivo could be developed as a sensitive, specific and quantifiable preclinical molecular imaging technique, and also whether this approach could be used to delineate the molecular effects of novel therapies. I utilised anti-E-selectin antibody labelled with NIR fluorophore in a mouse model of paw swelling induced by intra-plantar injection of TNF alpha, and in acute collagen-induced arthritis (CIA) in DBA/1 mice, a widely used model of RA. E-selectin generated signal, localised to points of maximal clinical inflammation in the inflamed mouse paw in both models with significant differences to control antibody. Binding of anti-E-selectin antibody was also demonstrated by immunohistochemistry in both models. The ability of E-selectin targeted imaging to detect sub-clinical endothelial activation was also investigated, demonstrating that E-selectin may be an excellent way of determining subclinical vascular activation in CIA. Finally the effect of novel targeted therapy – RB200 which blocks epidermal growth factor (EGF) signalling was investigated. This demonstrated that E-selectin targeted signal could be absolutely abrogated to a level seen in unimmunised healthy control animals, following combination treatment with RB200 and the TNF alpha inhibitor etanercept. E-selectin targeted optical imaging is a viable in vivo imaging technique that can also be applied to quantify disease and investigate the effects of novel molecular therapies. It holds significant promise as a molecular imaging technique for future translation into the clinic for patients with rheumatoid arthritis and other inflammatory diseases

More Than Skin Deep: Detection of subclinical enthesopathy and early psoriatic arthritis in patients with psoriasis in primary and secondary care and assessment of the response to anti-IL-12/IL-23p40 monoclonal antibody skin-directed therapy using ultrasound and whole-body MRI

Objectives: Primary care cohort: To determine the rates of undiagnosed psoriatic arthritis (PsA) amongst patients with psoriasis using clinical examination and screening questionnaires, and test the performance a new PsA screening questionnaire alongside the current standard (Psoriasis Epidemiology Screening Tool, PEST). Secondary care cohort: To develop novel ultrasound and whole body magnetic resonance imaging (WBMRI) protocols to facilitate the comprehensive assessment of subclinical abnormalities within the peripheral and axial skeleton of immunomodulatory therapy-naïve patients with psoriasis referred to secondary care, and to use these protocols to assess the imaging response of abnormalities over 52 weeks of skin- directed treatment with a licensed IL-12/23p40 inhibitor (ustekinumab). Methods: Primary care cohort: 932 patients, across five diverse primary care practices, who were coded as having a diagnosis of psoriasis, were invited by their General Practitioner to attend an evening appointment at their surgery for a consultation with a dermatologist and a rheumatologist. Half of patients were sent an educational leaflet regarding PsA with their invitation letter. Attendees were examined and asked to complete a PEST questionnaire and a new PsA screening questionnaire (CONTEST). Secondary care cohort: 73 immunomodulatory therapy-naive patients, without musculoskeletal disease or symptoms, who were referred to dermatology for treatment of moderate to severe psoriasis were screened using an extensive ultrasound protocol to assess for the presence of subclinical enthesitis. Patients who had at least one inflammatory abnormality, and in whom biologic therapy was not contraindicated, were invited to receive standard-dose skin directed therapy with ustekinumab for 52 weeks. Ultrasound examination of 13 entheses and structures within the adjacent synovio- entheseal complex were performed at weeks 0, 12, 24 and 52. WBMRI was performed at week 0, 24 and 52, to assess the axial skeleton and sites in the peripheral skeleton inaccessible by ultrasound. 23 healthy volunteers had one ultrasound scan and WBMRI using the same protocols, for comparison. Results: Primary care cohort: 20.5% of patients invited for screening attended. The provision of an educational leaflet did not have an impact on attendance for screening, except in the most deprived areas. 191 patients were examined, of which 169 had current or previous psoriasis (11.5% misdiagnosis rate). 17 patients were newly diagnosed with PsA (10.1%). The best sensitivity and specificity of the CONTEST questionnaires were 76.5% and 56.5% respectively, without the joint mannequin (cut off 33), and 70.6% and 63.3% respectively, with the joint mannequin (cut off 34). The sensitivity and specificity of the PEST questionnaire in this cohort, using the validated cut off 33, was 52.9% and 66.0%. Lowering the cut off 32, the sensitivity improved to 82.4% with a specificity of 44.9%. Secondary care cohort: 36 patients (49.3%) had at least inflammatory subclinical abnormality on screening ultrasound. 28 of these 36 were eligible for a biologic therapy and agreed to undergo a more detailed ultrasound scan and WBMRI. 5 patients subsequently chose conventional therapy, and 23 patients consented to treatment with ustekinumab and long-term review. 23 patients reached the primary end point of week 24, and 20 reached week 52. Inflammatory and chronic damage abnormalities were seen with greater frequency in the peripheral rather than axial skeleton, mostly involving the larger entheses of the knee, foot, ankle and elbows. Healthy volunteers exhibited a similar pattern of abnormalities but at a significantly lower frequency (inflammatory lesions 4.5% vs. 31.1%, chronic damage lesions 6.0% vs. 27.0%, both p<0.00001). Synovitis was seen in 82.1% of patients, while bursitis and tenosynovitis were uncommon. Following treatment with ustekinumab, ultrasound inflammation scores reduced by 42.2% at the primary end point (week 24, p<0.001), and by 51.5% after 52 weeks (p=0.01). Chronic damage scores remain unchanged (p=0.082 week 24, p=0.512 week 52). In the axial skeleton, more patients than volunteers had vertebral unit bone marrow oedema (64.3% vs. 30.4%, p<0.00001). Sacroiliac joint inflammation was minimal in both groups. Axial structural changes occurred in 14.3% in patients and were absent in volunteers. No significant change in spine or SIJ osteitis (p=0.656 week 24, p=0.627 week 52), or structural abnormalities were observed after ustekinumab therapy. Conclusions: A proportion of patients with psoriasis have undiagnosed PsA in primary care, even with signs and symptoms of inflammatory arthritis. Screening questionnaires are useful to detect some, but not all patients and further measures are required to capture all cases of PsA. Early identification and treatment is essential to prevent future pain, functional limitation and disability. Treating patients for psoriasis with a therapeutic agent that is effective at reducing the development of PsA is one means of addressing the failings of clinical examination and screening questionnaires, although the evolution from subclinical enthesitis (a common finding in patients with psoriasis) to PsA is not understood. This thesis provides preliminary data to suggest that anti-IL-12/23p40 therapy may reduce the burden of subclinical inflammation at the primary site of lesion development in PsA (the enthesis), and further longitudinal studies are now encouraged to confirm these observations with ustekinumab and other immunomodulatory therapies

Cellular and molecular heterogeneity in the synovial tissue of osteoarthritis patients

PhD ThesisOsteoarthritis (OA) is the most common form of arthritis and one of the leading causes of disability globally. There are no disease modifying treatments, and for end stage disease, total joint replacement is the only therapeutic option. There is a major unmet clinical need for OA patients. Compared to peripheral blood and inflammatory arthritis (IA), there has been less research into the cellular mechanisms and inflammatory processes involved in the synovial tissue of OA. A barrier to this research has been difficulty in isolating cells from tissues at the site of disease activity. I aimed to identify and compare the cellular phenotype, functional capacity and gene expression of synovial tissue mononuclear cell subsets in OA and IA. After assessing an array of published tissue digestion protocols, I developed a standardised synovial tissue digestion protocol allowing the isolation of multiple cell subsets with high yields, preserved cellular antigens and high cell viability. A multi-colour flow cytometry panel was established to allow the accurate identification and fluorescence-activated cell sorting of cDC2 dendritic cells, CD14+ monocytes, HLA-DR+CD14+ macrophages and CD4+ T cells. Computational analysis of flow cytometry data sets demonstrated greater cellular infiltrate in IA, but an increased proportion of macrophages in OA. However, this proportion was not seen in all OA patients. Owing to their increased but varied proportion, and previously described role in OA pathogenesis, I conducted an in-depth analyses of these cells. OA macrophages had higher expression of surface proteins associated with activation such as CD206, FOLR2 and CD86. Functionality of isolated macrophages was retained, demonstrated by their high phagocytic activity. Next generation RNA-sequencing was performed to better understand their function and heterogeneity in OA synovial tissue. Two distinctive OA endotypes were proposed based on functional gene signatures. One gene signature comprised of cell cycle and proliferation mechanisms, whilst the other consisted of cartilage and tissue development. Despite its central role in arthritic processes, the role of the synovium has remained obscure. This optimised digestion protocol now allows the interrogation of individual cell subsets. Analysis of synovial macrophages using this protocol has demonstrated distinct endotypes within OA patients. Improved investigation into the pathogenesis of OA, especially in the context of OA subtypes, can now be conducted. This could ultimately lead to the modification of treatment strategies for OA patients.Rheumatoid Arthritis pathogenesis Centre for Excellence (RACE - Arthritis Research UK) and JGW Patterson foundation (JGWP