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.

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.

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.

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.

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.

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 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.

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.

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.

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.

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.

Leptomeningitis in rheumatoid arthritis.

In this case report, we describe the case of a patient given the presumptive diagnosis of rheumatoid leptomeningitis on the basis of clinical findings and clinical response to antirheumatic medications after other causes of meningitis were excluded. Numerous case reports describe rheumatoid meningitis; however, rheumatoid leptomeningitis, in the absence of pachymeningitis, is a rare phenomenon. As such, the literature about it is scant. This unique case provides an opportunity to further characterize the symptoms and radiological findings of leptomeningitis in a patient with rheumatoid arthritis.

The utility of dual energy computed tomography in the management of axial gout: case reports and literature review.

BACKGROUND: Severe spinal pain is an unusual presentation of gout. Due to its rarity and the difficulty of obtaining joint fluid or tissue for crystal analysis, dual energy computed tomography (DECT) may be a useful imaging modality in the management of axial gout. CASE PRESENTATION: Two patients independently presented to a major teaching hospital with severe spinal pain subsequently shown to be due to gout. The first patient presented with back pain and fevers and was initially thought to have lumbar facet joint septic arthritis. The second case presented with severe back pain. In both cases, DECT suggested monosodium urate deposition in spinal tissues as the cause of their presentation. CONCLUSIONS: Axial gout should be considered in the differential diagnosis of severe spinal pain. A DECT study may be a useful diagnostic tool in the management of spinal gout.

IFNL3 genotype is associated with pulmonary fibrosis in patients with systemic sclerosis.

Fibrosis across different organs and tissues is likely to share common pathophysiological mechanisms and pathways. Recently, a polymorphism (rs12979860) near the interferon lambda gene (IFNL3) was shown to be associated with fibrosis in liver across multiple disease etiologies. We determined whether this variant is a risk factor for pulmonary fibrosis (PF) and worsening cutaneous fibrosis in systemic sclerosis (SSc). Caucasian patients with SSc (n = 733) were genotyped to test for association with the presence of PF and worsening of skin fibrosis. Serum IFN-λ3 levels from 200 SSc cases were evaluated. An association of the IFNL3 polymorphism with PF was demonstrated (OR: 1.66 (95% CI: 1.142-2.416, p = 0.008). The IFNL3 variant was not a risk factor for worsening of skin fibrosis. Functionally, IFN-λ3 serum levels were higher among subjects with PF compared to those unaffected (P < 0.0001). In conclusion, IFNL3 serum levels and the genetic variant known to be associated with liver fibrosis are similarly linked to PF, but not to worsening of skin fibrosis in SSc. These data highlight both common fibrosis pathways operating between organs, as well as differential effects within the same disease.