The burden of rheumatologic disease in Aboriginal and Torres Strait Islander Australians.

The objective of this article is to summarise the current knowledge regarding the prevalence of six rheumatological conditions in indigenous Australians - rheumatoid arthritis (RA), osteoarthritis (OA), osteoporosis (OSP), systemic lupus erythematosus (SLE), gout and musculoskeletal (MSK) pain. Online medical literature databases were searched for 'indigenous', 'Aboriginal' and 'Torres Strait Islander', as well as the names of the six conditions. Other included search terms were 'crystal', 'urate', 'arthritis' and 'arthropathy'. No limitations were placed on publication data or language. Forty-five articles examining the prevalence of the six conditions were identified. Based on the published literature, SLE appears to have a higher prevalence, while RA appears to have a lower prevalence in indigenous Australians compared to the non-indigenous community. MSK pain is prevalent, has a significant impact on indigenous people and is perceived as an important area of need. There is a paucity of data regarding these conditions in indigenous Australians. This may be impacted by the uncertainty of case ascertainment by self-report, differences in disease phenotypes and prevalence between the metropolitan compared to the rural or remote indigenous population, and difficulty with access to healthcare. Further studies in conjunction with local indigenous communities are needed to accurately determine the burden of rheumatological disease in the indigenous population. This will assist with resource and workforce planning to deliver culturally appropriate interventions. Strategies for future clinical work and research include the development and dissemination of culturally safe rheumatology resources, rheumatology training of Aboriginal Health Workers and wider integration of rheumatology clinics into community-controlled Aboriginal Health Services.

The disproportionately large contribution of the Maori and Pacific Islander community to the healthcare burden of gout in Western Sydney.

BACKGROUND: Gout is a common chronic inflammatory disorder due to monosodium urate deposition, which results in severe inflammatory arthritis. It is particularly common in those of Maori or Pacific Islander heritage. There is a significant number of this at-risk ethnic group in western Sydney. AIMS: To determine the healthcare burden of gout in Western Sydney. METHODS: We characterised patients managed in the emergency departments (EDs) of the four Western Sydney Local Health District (WSLHD) hospitals and those admitted for gout as the primary or secondary diagnosis from 1 January 2017 to 31 December 2018. RESULTS: There were 472 patients managed in ED on 552 occasions at a direct cost to the LHD of A$367 835. Those of Maori or Pacific Islander ethnicity comprised 25.2% (n = 119/472), while half (n = 39/80) of those managed in ED for gout on two or more occasions were of Maori or Pacific Islander ethnicity. Overall, 310 patients were admitted with gout as the principal diagnosis on 413 occasions at a cost of A$1.73 million. Seventy-five (24.2%) of the 310 patients were of Maori or Pacific Islander heritage. A total of 584 WSLHD inpatients had gout as a secondary diagnosis. This was associated with 714 admissions. CONCLUSIONS: The disproportionately large healthcare burden of gout in Western Sydney from the relatively small Maori and Pacific Islander population needs attention. Urgent culturally appropriate interventions to address gout are required to address this inequality.

Non-Antigenic Modulation of Antigen Receptor (TCR) Cß-FG Loop Modulates Signalling: Implications of External Factors Influencing T-Cell Responses.

T-cell recognition of antigens is complex, leading to biochemical and cellular events that impart both specific and targeted immune responses. The end result is an array of cytokines that facilitate the direction and intensity of the immune reaction-such as T-cell proliferation, differentiation, macrophage activation, and B-cell isotype switching-all of which may be necessary and appropriate to eliminate the antigen and induce adaptive immunity. Using in silico docking to identify small molecules that putatively bind to the T-cell Cß-FG loop, we have shown in vitro using an antigen presentation assay that T-cell signalling is altered. The idea of modulating T-cell signalling independently of antigens by directly targeting the FG loop is novel and warrants further study.

Musculoskeletal immune-related adverse events with the use of checkpoint inhibitors in malignancy.

BACKGROUND: Immunotherapy has revolutionised the treatment of many malignancies. Along with their success, there have been inflammatory and immune-related adverse events (irAE). There is a paucity of literature describing the Australian experience of rheumatic irAE. AIMS: To describe and characterise the Royal North Shore Hospital and Westmead Hospital cohort with rheumatic irAE. METHODS: This case series reports on 17 patients with advanced cancer treated at two sites in Sydney, Australia who were referred for rheumatological evaluation from 2013 to 2016. Data were collected retrospectively and inspected for clinical signs, duration of immunotherapy prior to onset of symptoms, management strategies and cancer outcomes. RESULTS: Patients presented with arthralgias, myalgias, periarticular and systemic symptoms. Onset of rheumatological symptoms was variable, with a median of 4 months (range 0.2-24) for monotherapy and 5.05 months (range 0.2-6.9) for combination. The predominant findings were of tenosynovitis (23%) and large joint involvement (65%). All patients were seronegative for RF and anti-CCP. Most patients responded well to non-steroidal anti-inflammatory drugs or low-dose prednisone (59%) and remained on immunotherapy (77%). The majority (76%) of patients experienced concomitant irAE in other organ systems. Sixty-five percent of patients had complete response of their malignancy to immunotherapy. CONCLUSION: Rheumatic irAE are heterogenous clinical entities, which require further evaluation into classification, patient susceptibility and response. From our study, there was no clear clinical pattern. The present case series supports that rheumatic irAE may be associated with tumour response. However, there is still limited experience in rheumatic irAE management and outcomes.

Epstein-Barr virus-related lymphoma in rheumatoid arthritis: implications for long-term usage of immunosuppressive drugs and review of the literature.

BACKGROUND: Rheumatoid arthritis (RA) is a common autoimmune disease where methotrexate (MTX) is widely used as the first-line therapy. The combination of RA and MTX is associated with lymphoproliferative disorders (LPD). RA patients with Epstein-Barr virus (EBV) have impaired T-lymphocyte function, thus allowing an overgrowth of EBV-positive lymphoblastoid cells. We examined the association of EBV with LPD in immunosuppressed RA patients, particularly those treated with MTX. AIM: To review the relationship between RA, EBV-associated LPD and MTX use. METHODS: We reported two cases of RA patients with long-term MTX treatment who subsequently developed EBV-positive LPD, followed by a review of the relevant literature. RESULTS: Compared with normal population, RA patients have a higher risk of lymphoma, with diffuse large B-cell lymphoma being the most common subtype. MTX withdrawal can lead to lymphoma regression. Other biological therapies, such as abatacept and tocilizumab, are not associated with increased EBV-positive lymphoma diagnosis in RA patients. CONCLUSION: The association between EBV, lymphoma and MTX highlights the need to consider reducing or stopping MTX in patients who have had stable RA for many years.

Acute arthritis: predictive factors and current practice in the approach to diagnosis and management across two hospitals in Sydney.

BACKGROUND: Literature pertaining to the predictive factors for septic arthritis is limited. AIMS: The primary objective was to investigate the predictive factors for septic arthritis. The secondary objectives were to investigate the predictive factors for crystal arthritis and to explore current practices in the management of acute arthritis. METHODS: A retrospective analysis was undertaken. All patients with an acute arthritis who underwent a joint aspiration for diagnostic and management purposes were considered for inclusion. The outcome measures were patient demographics, findings on physical examination, findings on blood and synovial fluid analysis and management. RESULTS: Of the patients who presented with an acute arthritis, 24 of the 172 joint aspirations undertaken were positive for bacteria (13.95%). Of the 172 joint aspirations, 90 were positive for crystals (52.33%). Investigated variables associated with increased risk for the presence of bacteria on synovial fluid included features of sepsis (P < 0.001), joint-restricted range of motion (P = 0.048), elevated C-reactive protein (P < 0.001) and elevated total leukocyte count on synovial fluid (P < 0.001). Of the 24 joint aspirations that were positive for bacteria, 13 had associated positive blood cultures (54.17%). Of the 172 joint aspirations, antibiotics were administered in 96 cases (55.81%). Of these, antibiotics were administered prior to joint aspiration in 41 cases (42.71%). CONCLUSIONS: In our study, the most common cause of acute arthritis was crystal arthropathy. An accurate physical examination in conjunction with synovial fluid analysis is of particular importance in diagnosing septic arthritis. Blood cultures are not a reliable substitute for joint aspiration but should nevertheless be undertaken.

Cyclization enhances function of linear anti-arthritic peptides.

This study describes the biophysical and immunomodulatory features of a cyclic peptide termed C1 which consists of alternating d-, l-amino acids and is capable of inhibiting IL-2 production in vitro and reducing the induction and extent of T-cell mediated inflammation in animal models. Solid-state nuclear magnetic resonance demonstrates that the peptide orders the lipid bilayer, suggesting a transmembrane orientation, and this is supported by surface plasmon resonance indicating strong binding affinity of C1 to model membranes. In vitro cell viability and proliferation assays show that C1 does not disrupt the integrity of cell surface membranes. Permeation studies of C1 and analogs across human epidermis cells show that the stability and skin permeability are enhanced by cyclization. Treatment with C1 in an asthma and in an arthritis animal model resulted in a suppressed immune response. Cyclization may be a useful means of enhancing biological linear peptide activity and improving delivery.

Prevalence, Severity, and Measures of Anxiety in Rheumatoid Arthritis: A Systematic Review.

OBJECTIVE: Many studies have reported high rates of anxiety in adults with rheumatoid arthritis (RA). The aim of this systematic review was to examine those findings and determine the overall prevalence, severity, and commonly used measures of anxiety in individuals with RA. METHODS: Six databases were searched from January 2000 without restrictions on language/location, study design, or gray literature. All identified studies that examined anxiety prevalence and severity in adults with RA, as assessed with clinical diagnostic interview and/or standardized self-report measures, were considered for inclusion. Quality assessment of included studies was conducted using a modified Newcastle-Ottawa Evaluation Scale, and the findings were synthesized via a narrative approach. RESULTS: Across the 47 studies (n = 11,085 participants), the sample size ranged from 60 to 1,321 participants with seven studies including healthy controls or groups with other health conditions. The studies were conducted across 23 countries, and anxiety prevalence ranged from 2.4% to 77%, predominantly determined with standardized self-report measures, of which Hospital Anxiety and Depression scale was used most frequently; only eight studies used a clinical diagnostic interview to confirm a specific anxiety diagnosis. Notable associations with anxiety in RA were physical disability, pain, disease activity, depression, and quality of life. CONCLUSION: The reported prevalence of anxiety in RA varied widely potentially because of use of different self-report measures and cutoff points. Such cutoff points will need to be standardized to clinical thresholds to inform appropriate interventions for anxiety comorbidity in RA.

Effectiveness of Moving On: an Australian designed generic self-management program for people with a chronic illness.

BACKGROUND: This paper presents the evaluation of "Moving On", a generic self-management program for people with a chronic illness developed by Arthritis NSW. The program aims to help participants identify their need for behaviour change and acquire the knowledge and skills to implement changes that promote their health and quality of life. METHOD: A prospective pragmatic randomised controlled trial involving two group programs in community settings: the intervention program (Moving On) and a control program (light physical activity). Participants were recruited by primary health care providers across the north-west region of metropolitan Sydney, Australia between June 2009 and October 2010. Patient outcomes were self-reported via pre- and post-program surveys completed at the time of enrolment and sixteen weeks after program commencement. Primary outcomes were change in self-efficacy (Self-efficacy for Managing Chronic Disease 6-Item Scale), self-management knowledge and behaviour and perceived health status (Self-Rated Health Scale and the Health Distress Scale). RESULTS: A total of 388 patient referrals were received, of whom 250 (64.4%) enrolled in the study. Three patients withdrew prior to allocation. 25 block randomisations were performed by a statistician external to the research team: 123 patients were allocated to the intervention program and 124 were allocated to the control program. 97 (78.9%) of the intervention participants commenced their program. The overall attrition rate of 40.5% included withdrawals from the study and both programs. 24.4% of participants withdrew from the intervention program but not the study and 22.6% withdrew from the control program but not the study. A total of 62 patients completed the intervention program and follow-up evaluation survey and 77 patients completed the control program and follow-up evaluation survey. At 16 weeks follow-up there was no significant difference between intervention and control groups in self-efficacy; however, there was an increase in self-efficacy from baseline to follow-up for the intervention participants (t=-1.948, p=0.028). There were no significant differences in self-rated health or health distress scores between groups at follow-up, with both groups reporting a significant decrease in health distress scores. There was no significant difference between or within groups in self-management knowledge and stage of change of behaviours at follow-up. Intervention group attenders had significantly higher physical activity (t=-4.053, p=0.000) and nutrition scores (t=2.315, p= 0.01) at follow-up; however, these did not remain significant after adjustment for covariates. At follow-up, significantly more participants in the control group (20.8%) indicated that they did not have a self-management plan compared to those in the intervention group (8.8%) (X²=4.671, p=0.031). There were no significant changes in other self-management knowledge areas and behaviours after adjusting for covariates at follow-up. CONCLUSIONS: The study produced mixed findings. Differences between groups as allocated were diluted by the high proportion of patients not completing the program. Further monitoring and evaluation are needed of the impact and cost effectiveness of the program. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry: ACTRN12609000298213.

Anti-inflammatory Effects of First-line Anti-arthritic Drugs on T-cell Activation.

AIM: The in vitro effects of commonly used first-line anti-arthritic drugs on early stages of T-cell activation were examined. METHODS: The 2B4.11 murine T cell hybridoma cell line recognizing pigeon cytochrome c (PCC) as the antigen was co-cultured with the histocompatible antigen presenting B cell hybridoma line LK35.2, PCC, and anti-arthritic drugs, including methotrexate, hydroxychloroquine, salazopyrine, cyclosporin, and leflunomide. After 16 hours of incubation, the supernatant was removed, and cytokines were assayed. RESULTS: Anti-arthritic drugs inhibited the production of pro-inflammatory cytokines IL-2, IL-6, IFN-γ, GM-CSF, and TNF-α (Th1 cytokines) to a varying extent. Surprisingly, leflunomide, salazopyrine, prednisone and indomethacin as well as blocking Th1 cytokines, stimulated the production of the anti-inflammatory cytokine IL-10, a Th2 cytokine. CONCLUSION: Anti-arthritic medications can inhibit the production of pro-inflammatory cytokines and in some cases, incite a Th2 response that could potentially inhibit the progression of the immune response.

The role of ion channels in T cell function and disease.

T lymphocytes (T cells) are an important sub-group of cells in our immune system responsible for cell-mediated adaptive responses and maintaining immune homeostasis. Abnormalities in T cell function, lead the way to the persistence of infection, impaired immunosurveillance, lack of suppression of cancer growth, and autoimmune diseases. Ion channels play a critical role in the regulation of T cell signaling and cellular function and are often overlooked and understudied. Little is known about the ion "channelome" and the interaction of ion channels in immune cells. This review aims to summarize the published data on the impact of ion channels on T cell function and disease. The importance of ion channels in health and disease plus the fact they are easily accessible by virtue of being expressed on the surface of plasma membranes makes them excellent drug targets.

Biologics in peripheral ulcerative keratitis.

Over the past two decades biologic therapies have seen a rapid uptake in the management of ocular inflammation. Peripheral ulcerative keratitis (PUK), once a harbinger of blindness and mortality in refractory rheumatological disease, is now increasingly being treated with these agents. We conducted a review to evaluate the evidence base for this application and to provide a road map for their clinical usage in PUK, including dosage and adverse effects. A literature search across Medline, Embase and Cochrane Database of Systematic Reviews was undertaken to identify all patients with PUK that were treated with a biologic in a peer viewed article. Overall, whilst the evidence base for biologic use in PUK was poor, reported cases demonstrate an increasingly powerful and effective role for biologics in refractory PUK. This was particularly the case for rituximab in PUK secondary to granulomatous with polyangiitis.

Cardiac sarcoma presenting as paraneoplastic arthritis and clubbing: a case report and literature review.

BACKGROUND: Cardiac tumours are rare, and clinical manifestations depend on the anatomical location. Symptoms can be the result of cardiac outflow anomalies, constitutional features such as fever, loss of weight, and/or paraneoplastic manifestations such as arthritis. To date, there has only been one other case report in the literature of cardiac sarcoma presenting as paraneoplastic arthropathy. CASE PRESENTATION: A 52-year-old woman presented with acute onset corticosteroid-resistant inflammatory polyarthralgia, clubbing and a systolic murmur. Transthoracic echocardiogram revealed a dilated left atrium with an echogenic mass and brain magnetic resonance imaging revealed multiple embolic infarcts. Histopathology following emergency resection showed a Grade 3 left atrial intimal sarcoma. The polyarthralgia and clubbing resolved soon after tumour removal. The patient went on to receive chemotherapy and remains in remission. CONCLUSIONS: This case highlights the rare paraneoplastic association of cardiac sarcoma and arthropathy.

The spectrum of cutaneous polyarteritis nodosa. A case report of two contrasting cases and review of the literature.

Cutaneous polyarteritis nodosa is a rare neutrophilic vasculitis. We present two cases that reflect the gamut of this disorder including one case whose delayed diagnosis led to permanent nerve deficit and scarring.

The diagnostic accuracy of temporal artery ultrasound and temporal artery biopsy in giant cell arteritis: A single center Australian experience over 10 years.

AIM: To assess the diagnostic accuracy of temporal artery ultrasound compared with temporal artery biopsy and clinical diagnosis in patients with suspected giant cell arteritis (GCA) over 10 years in an Australian center. METHOD: Patients presenting to Westmead Hospital with possible GCA from March 2011 to December 2020 were retrospectively identified. The following parameters were obtained from the medical record: clinical presentation, inflammatory markers, temporal artery ultrasound findings, and temporal artery biopsy report. Data were assembled in a 2 × 2 table; sensitivity and specificity of temporal artery ultrasound compared with temporal artery biopsy and clinical diagnosis were calculated. RESULTS: Over the 10-year study period, 65 temporal artery ultrasounds were performed in 63 patients (n = 65; 61.9% female) with a mean ± standard deviation age of 69.6 ± 12.3 years. Thirteen out of 65 (20%) temporal artery ultrasounds had findings suggestive of GCA. Twenty patients (31.7%) had a clinical diagnosis of GCA irrespective of sonographic or biopsy findings. Compared with temporal artery biopsy, temporal artery ultrasound had a sensitivity of 71.4% and specificity of 93.3%. Compared with clinical diagnosis made by the treating rheumatologist, temporal artery ultrasound had a sensitivity of 55% and specificity of 95.3%. CONCLUSION: Temporal artery ultrasound is a useful non-invasive investigation in the assessment of suspected GCA. If positive in the setting of a suggestive clinical presentation, a temporal artery ultrasound probably avoids the need for a temporal artery biopsy. Temporal artery ultrasound could be more widely used in the clinical management of GCA.

An enquiry into the crippling gout affecting Pacific Islander and Maori men in Western Sydney.

AIM: Despite the effectiveness and availability of urate-lowering therapies (ULT), we continue to see a number of advanced cases of tophaceous gout in the Pacific Islander and Maori population in Western Sydney. Although the high prevalence and increased severity of gout in this cohort has been well documented, there has been little qualitative research undertaken in Australia into the lived experience of this group of people. It is this gap in the research that our study aimed to address. METHODS: Participants were recruited from the rheumatology clinics at Westmead and Blacktown Hospitals. Those eligible to participate were Pacific Islander and Maori patients with tophaceous gout currently living in the Western Sydney Local Health District (WSLHD). Data collection took the form of 10 semi-structured interviews, which were subsequently transcribed verbatim. A thematic analysis of the data was then performed. RESULTS: Thematic analysis identified 6 key themes: lack of understanding of the disease and its potential effects; missed opportunities for intervention and disjointed care; chronic reliance upon corticosteroids; trivialization of gout as a nuisance illness; the substantial financial impact of chronic illness; and the all-consuming nature of severe gout. CONCLUSION: The human cost of severe tophaceous gout in this cohort is immense. All 10 participants exemplified the disease's devastating social effects. We propose 4 key recommendations: improved education regarding diagnosis and management; immediate prescription of ULT at first presentation; a lower threshold for out-of-hospital rheumatologist referral; and improved follow-up through a nurse- and pharmacist-led collaborative gout management program.