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1.
Ir J Med Sci ; 193(1): 443-448, 2024 Feb.
Article in English | MEDLINE | ID: mdl-37418106

ABSTRACT

BACKGROUND: Axial spondyloarthritis (axSpA) comprises patients with both radiographic and non-radiographic features. Previous studies have shown similar burden of disease between these two groups. AIMS: The Ankylosing Spondylitis Registry of Ireland (ASRI) was formed with the objective to measure the burden of axial spondyloarthritis in the population and identify early predictors of a poor outcome. For this analysis, the ASRI database was used to compare the characteristics and burden of disease in patients with radiographic versus non-radiographic axial spondyloarthritis. METHODS: Patients with radiographic axial spondyloarthritis (r-axSpA) were defined as those with X-ray evidence of sacroiliitis. Patients with non-radiographic axial spondyloarthritis (nr-axSpA) were defined as having MRI evidence of sacroiliitis but no X-ray evidence of sacroiliitis. RESULTS: In total, 764 patients were included. Analysis of radiographic status showed 88.1% (n = 673) of patients with r-axSpA and 11.9% (n = 91) with nr-axSpA (Table 1). Patients with nr-axSpA were younger (41.3 vs. 46.6 years, p < 0.01), had shorter disease duration (14.8 vs. 20.2 years, p < 0.01) and had lower proportion of males (66.6% vs. 78.4%, p = 0.02) with lower frequency of HLA-B27 positivity (73.6% vs. 90.5%, p < 0.01). The nr-axSpA group had lower BASDAI (3.37 vs. 4.05, p = 0.01), BASFI (2.46 vs. 3.88, p < 0.01), BASMI (2.33 vs. 4.34, p < 0.01), ASQoL (5.2 vs. 6.67, p = 0.02) and HAQ scores (0.38 vs. 0.57, p < 0.01). There were no significant differences in the prevalence of extra-musculoskeletal manifestations or use of medications. CONCLUSIONS: This study provides evidence to suggest that the burden of disease is less in patients with non-radiographic axial spondyloarthritis than radiographic axial spondyloarthritis.


Subject(s)
Non-Radiographic Axial Spondyloarthritis , Sacroiliitis , Spondylarthritis , Spondylitis, Ankylosing , Male , Humans , Spondylitis, Ankylosing/drug therapy , Spondylarthritis/drug therapy , Spondylarthritis/epidemiology , Ireland , Registries , Cost of Illness
2.
Chest ; 162(3): e111-e116, 2022 09.
Article in English | MEDLINE | ID: mdl-36088095

ABSTRACT

CASE PRESENTATION: A 45-year-old man sought treatment at the ED during the third wave of the COVID-19 pandemic with a month-long history of fatigue, cough, myalgia, and hand stiffness. He did not report dyspnea. He had no past medical history and previously was fit and active, working as a farmer. He was a lifelong nonsmoker and had no family history of lung disease.


Subject(s)
COVID-19 , Lung Diseases, Interstitial , COVID-19/complications , Dyspnea/diagnosis , Dyspnea/etiology , Humans , Lung Diseases, Interstitial/diagnosis , Male , Middle Aged , Myalgia/etiology , Pandemics
3.
Eur J Ophthalmol ; 31(2): 727-733, 2021 Mar.
Article in English | MEDLINE | ID: mdl-31957482

ABSTRACT

OBJECTIVE: To establish if there is a difference in health-related quality of life and vision-related quality of life in patients with a confirmed diagnosis of giant cell arteritis compared with those with clinical features suspicious for the disease at initial presentation but in whom giant cell arteritis is ultimately excluded. METHODS: A cross-sectional study of 116 patients who presented to two tertiary referral hospitals in Ireland with symptoms suspicious for giant cell arteritis was performed between August 2011 and June 2017. The Vision Core Measurement 1 and Short Form-36 questionnaires were used as assessment tools. RESULTS: The mean (standard deviation) age of all 116 participants was 69.4 (9.3) years of whom 74 (63.8%) were female. In the giant cell arteritis group, 19.7% had permanent loss of vision and 54.7% had non-permanent visual disturbance. Vision Core Measurement 1 score in the giant cell arteritis group correlated with worse eye visual acuity (r = 0.4233, p = 0.0002). The Short Form-36 subscales of role physical (p = 0.0002), role emotional (p = 0.024), and the mental composite score (p = 0.012) were significantly worse in patients with giant cell arteritis. A significant correlation was found between vision-related quality of life scores and all Short Form-36 subscale scores except bodily pain (r = -0.215 to -0.399, p < 0.05 for all), and between social functioning and visual acuity in the better eye (r = -0.242, p = 0.038). CONCLUSION: Vision-related quality of life is an important subjective concern for both patients presenting with a suspicion of giant cell arteritis and those with a definite diagnosis of giant cell arteritis. Features of giant cell arteritis impact on patients' physical and emotional states and vision influences global quality of life in giant cell arteritis. A long-term multidisciplinary approach is warranted for clinical, physical, and psychological treatment and support.


Subject(s)
Giant Cell Arteritis/physiopathology , Health Status , Quality of Life , Vision Disorders/physiopathology , Visual Acuity , Aged , Cross-Sectional Studies , Female , Giant Cell Arteritis/complications , Giant Cell Arteritis/diagnosis , Humans , Male , Surveys and Questionnaires , Vision Disorders/diagnosis , Vision Disorders/etiology
4.
Rheumatology (Oxford) ; 60(2): 902-906, 2021 02 01.
Article in English | MEDLINE | ID: mdl-33164088

ABSTRACT

OBJECTIVES: To establish, amongst Irish rheumatic musculoskeletal disease (RMD) patients, rates of COVID-19 symptoms and positive tests, DMARD adherence and attitudes to virtual clinics. METHODS: An online survey assessing COVID-19 status, RMD diagnoses, adherence and information sources was disseminated via the Arthritis Ireland website and social media channels. RESULTS: There were 1381 respondents with 74.8% on immunosuppressive medication. Symptoms of COVID-19 were reported by 3.7% of respondents of which 0.46% tested positive, consistent with the general Irish population. The frequency of COVID-19 symptoms was higher for respondents with spondyloarthropathy [odds ratio (OR) 2.06, 95% CI: 1.14, 3.70] and lower in those on immunosuppressive medication (OR 0.48, 95% CI: 0.27, 0.88), and those compliant with health authority (HSE) guidance (OR 0.47, 95% CI: 0.25, 0.89). Adherence to RMD medications was reported in 84.1%, with 57.1% using health authority guidelines for information on medication use. Importantly, adherence rates were higher amongst those who cited guidelines (89.3% vs 79.9%, P <0.001), and conversely lower in those with COVID-19 symptoms (64.0% vs 85.1%, P =0.009). Finally, the use of virtual clinics was supported by 70.4% of respondents. CONCLUSION: The rate of COVID-19 positivity in RMD patients was similar to the general population. COVID-19 symptoms were lower amongst respondents on immunosuppressive medication and those adherent to medication guidelines. Respondents were supportive of HSE advice and virtual clinics.


Subject(s)
Antirheumatic Agents/therapeutic use , Attitude to Health , COVID-19/epidemiology , Medication Adherence/statistics & numerical data , Rheumatic Diseases/drug therapy , Adult , Arthritis, Rheumatoid/drug therapy , Biological Products/therapeutic use , COVID-19/physiopathology , Chloroquine/therapeutic use , Connective Tissue Diseases/drug therapy , Cross-Sectional Studies , Female , Glucocorticoids/therapeutic use , Humans , Hydroxychloroquine/therapeutic use , Ireland/epidemiology , Janus Kinase Inhibitors/therapeutic use , Male , Middle Aged , SARS-CoV-2 , Spondylarthropathies/drug therapy , Telemedicine , Vasculitis/drug therapy
5.
Trials ; 21(1): 758, 2020 Sep 03.
Article in English | MEDLINE | ID: mdl-32883328

ABSTRACT

OBJECTIVES: Tocilizumab is a humanized monoclonal antibody which targets and inhibits interleukin-6 (IL-6) and has demonstrated efficacy in treating diseases associated with hyper-inflammation. Data are suggestive of tocilizumab as a potential treatment for patients with COVID-19 infection. The aim of this study is to determine the safety and efficacy of standard dose versus low dose tocilizumab in adults with severe, non-critical, PCR-confirmed COVID-19 infection with evidence of progressive decline in respiratory function and evolving systemic inflammation on time to intubation, non-invasive ventilation and/or all-cause mortality. TRIAL DESIGN: This trial is a phase 2, open label, two-stage, multicentre, randomised trial. PARTICIPANTS: Adult subjects with severe, non-critical, PCR-confirmed COVID-19 infection with evidence of progressive decline in respiratory function and evolving systemic inflammation requiring admission to hospital at St. Vincent's University Hospital and Mater Misericordiae University Hospital, Dublin, Ireland. Inclusion criteria Aged 18 years or older. Confirmed SARS-CoV2 infection (as defined by positive PCR). Evidence of hyper inflammatory state as evidenced by at least three of the following: Documented temperature >38°C in the past 48 hours, IL6 >40 pg/ml, or in its absence D-dimer >1.5 µgFEU /ml, Elevated CRP (>100mg/L) and/or a three-fold increase since presentation, Elevated ferritin X5 ULN, Elevated LDH (above the ULN), Elevated fibrinogen (above the ULN). Pulmonary infiltrates on chest imaging. Moderate to severe respiratory failure as defined by PaO2/FiO2≤300mmHg. INTERVENTION AND COMPARATOR: Intervention for participants in this trial is SOC plus Tocilizumab compared to SOC alone (comparator). For Stage 1, following randomisation, subjects will receive either (Arm 1) SOC alone or (Arm 2) SOC plus Tocilizumab (standard single dose - 8mg/kg, infused over 60 minutes. Once stage 1 has fully recruited, subsequent participants will be enrolled directly into Stage 2 and receive either (Arm 1) SOC plus Tocilizumab (standard single dose - 8mg/kg, infused over 60 minutes or (Arm 2) SOC plus Tocilizumab (standard single dose - 4mg/kg, infused over 60 minutes). MAIN OUTCOMES: The primary endpoint for this study is the time to a composite primary endpoint of progression to intubation and ventilation, non-invasive ventilation or death within 28 days post randomisation. RANDOMISATION: Eligible patients will be randomised (1:1) using a central register. Randomisation will be performed through an interactive, web-based electronic data capturing database. In stage 1, eligible participants will be randomised (1:1) to (Arm 1) SOC alone or to (Arm 2) SOC with single dose (8mg/kg, maximum 800mg) intravenous tocilizumab infused over 60 minutes. In stage 2, eligible participants will be randomised (1:1) to receive either (Arm 1) single, standard dose (8mg/kg, maximum 800mg) intravenous tocilizumab infused over 60 minutes or (Arm 2) reduced dose (4mg/kg, maximum 800mg) intravenous tocilizumab infused over 60 minutes. BLINDING: This study is open label. The study will not be blinded to investigators, subjects, or medical or nursing staff. The trial statistician will be blinded for data analysis and will be kept unaware of treatment group assignments. To facilitate this, the randomisation schedule will be drawn up by an independent statistician and objective criteria were defined for the primary outcome to minimize potential bias. NUMBERS TO BE RANDOMISED: In stage 1, 90 subjects will be randomised 1:1, 45 to SOC and 45 subjects to SOC plus Tocilizumab (8mg/kg, infused over 60 minutes). In stage 2, sample size calculation for the dose evaluation stage will use data generated from stage 1 using the same primary endpoint as in stage 1. TRIAL STATUS: The COVIRL002 trial (Protocol version 1.4, 13th May 2020) commenced in May 2020 at St. Vincent's University Hospital and Mater Misericordiae University Hospital, Dublin, Ireland. Recruitment is proceeding with the aim to achieve the target sample size on or before April 2021. TRIAL REGISTRATION: COVIRL002 was registered 25 June 2020 under EudraCT number: 2020-001767-86 and Protocol identification: UCDCRC/20/02. FULL PROTOCOL: The full protocol for COVIRL002 is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol. The study protocol has been reported in accordance with the Standard Protocol Items: Recommendations for Clinical Interventional Trials (SPIRIT) guidelines (Additional file 2).


Subject(s)
Anti-Inflammatory Agents/therapeutic use , Antibodies, Monoclonal, Humanized/therapeutic use , Betacoronavirus/drug effects , Coronavirus Infections/drug therapy , Pneumonia, Viral/drug therapy , Anti-Inflammatory Agents/adverse effects , Antibodies, Monoclonal, Humanized/adverse effects , Betacoronavirus/pathogenicity , COVID-19 , Clinical Trials, Phase II as Topic , Coronavirus Infections/diagnosis , Coronavirus Infections/mortality , Coronavirus Infections/virology , Disease Progression , Host Microbial Interactions , Humans , Intubation, Intratracheal , Ireland , Multicenter Studies as Topic , Pandemics , Pneumonia, Viral/diagnosis , Pneumonia, Viral/mortality , Pneumonia, Viral/virology , Randomized Controlled Trials as Topic , Respiration, Artificial , SARS-CoV-2 , Severity of Illness Index , Time Factors , Treatment Outcome , COVID-19 Drug Treatment
7.
Obstet Med ; 13(2): 96-100, 2020 Jun.
Article in English | MEDLINE | ID: mdl-32714443

ABSTRACT

Antisynthetase syndrome is a rare autoimmune, multisystem, inflammatory condition, characterised by autoantibodies against aminoacyl tRNA synthetases. The predominant features are myositis and interstitial lung disease but other symptoms such as Raynaud's phenomenon may also be present. Described here is a 36-year-old woman with antisynthetase syndrome who planned and underwent a successful pregnancy, during which a multidisciplinary team approach secured a good outcome for both mother and baby.

8.
Rheumatol Adv Pract ; 3(1): rkz011, 2019.
Article in English | MEDLINE | ID: mdl-31431999

ABSTRACT

OBJECTIVE: The aim of this study was to examine the pro-inflammatory effects of IL-6 in ex vivo temporal artery explant cultures. METHODS: Patients meeting 1990 ACR classification criteria for GCA were prospectively recruited. Temporal artery biopsies were obtained and temporal artery explants cultured ex vivo with IL-6 (10-40 ng/ml) in the presence or absence of its soluble receptor (sIL-6R; 20 ng/ml) for 24 h. Explant supernatants were harvested after 24 h and assayed for IFN-γ, TNF-α, Serum amyloid A, IL-1ß, IL-17, IL-8, angiotensin II and VEGF by ELISA. Myofibroblast outgrowths, cytoskeletal rearrangement and wound repair assays were performed. RESULTS: IL-6 augmented production of VEGF, but not of any of the other pro-inflammatory mediators assayed. No differences were observed in the explants cultured in the presence or absence of the sIL-6R or between those with a positive (n = 11) or negative (n = 17) temporal artery biopsy. IL-6 did not enhance myofibroblast proliferation or migration. Western blot analysis confirmed signalling activation, with increased expression of pSTAT3 in response to IL-6+sIL-6R. CONCLUSION: IL-6 stimulation of temporal artery explants from patients with GCA neither increased expression of key pro-inflammatory mediators nor influenced myofibroblast proliferation or migration.

10.
Clin Exp Rheumatol ; 37 Suppl 117(2): 72-78, 2019.
Article in English | MEDLINE | ID: mdl-30620296

ABSTRACT

OBJECTIVES: The diagnosis of giant cell arteritis (GCA) is primarily a clinical one. Temporal artery (TA) ultrasound (US) has been proposed as a new diagnostic tool. We aimed to assess the performance characteristics of TA US in routine clinical practice. METHODS: All patients presenting with suspected GCA to our institution are recruited to a prospective registry. Patients who had both a TA US and biopsy (TAB) performed at the time of presentation were included in the current study. The performance characteristics of TA US was compared to physician diagnosis at six months following presentation. Predictive factors for a positive TA US were explored in univariate and multivariable logistic regression analyses. RESULTS: 162 patients were included, 123 (76%) with GCA. Mean (SD) duration of glucocorticoid therapy was 6.6 days (19.4) at the time of TA US. TA US had a sensitivity of 52.8% (95%CI 43.7, 61.9) and specificity of 71.8% (95%CI 54.9, 84.5) for the diagnosis of GCA. Glucocorticoid duration did not significantly impact the results. A sequential strategy of TA US followed by TAB in the case of a negative US had a sensitivity of 78.9% (95%CI 70.1, 85.5) and specificity of 71.8% (95%CI 54.9, 84.5), equivalent to a simultaneous testing strategy. The only factor independently predictive of a positive TA US was male sex (OR 5.53, 95% CI 2.72 to 11.22, p<0.001). CONCLUSIONS: TA US is potentially useful in the diagnosis of GCA; however, interpretation of its results requires knowledge of the performance characteristics in the target population.


Subject(s)
Giant Cell Arteritis , Temporal Arteries , Ultrasonography/methods , Biopsy , Cohort Studies , Female , Giant Cell Arteritis/diagnosis , Humans , Male , Prospective Studies , Temporal Arteries/diagnostic imaging
11.
Ann Rheum Dis ; 77(12): 1815-1824, 2018 12.
Article in English | MEDLINE | ID: mdl-30097452

ABSTRACT

OBJECTIVES: The pathogenesis of giant cell arteritis (GCA) remains unclear. TH1 and TH17 pathways are implicated, but the proximal initiators and effector cytokines are unknown. Our aim was to assess the role of interleukin 12 (IL-12) and interleukin 23 (IL-23) in GCA pathogenesis. METHODS: IL-12 and IL-23 expression were quantified by immunohistochemistry in temporal artery biopsies (TABs). Temporal artery (TA) explant, peripheral blood mononuclear cell (PBMC) and myofibroblast outgrowth culture models were established. PBMCs and TA explants were cultured for 24 hours in the presence or absence of IL-12 (50 ng/mL) or IL-23 (10 ng/mL). Gene expression in TA was quantified by real-time PCR and cytokine secretion by ELISA. Myofibroblast outgrowths were quantified following 28-day culture. RESULTS: Immunohistochemistry demonstrated increased expression of interleukin 12p35 (IL-12p35) and interleukin 23p19 (IL-23p19) in biopsy-positive TAs, localised to inflammatory cells. IL-12p35 TA expression was significantly increased in those with cranial ischaemic complications (p=0.026) and large vessel vasculitis (p=0.006). IL-23p19 TA expression was increased in those with two or more relapses (p=0.007). In PBMC cultures, exogenous IL-12 significantly increased interleukin 6 (IL-6) (p=0.009), interleukin 22 (IL-22) (p=0.003) and interferon γ (IFN-γ) (p=0.0001) and decreased interleukin 8 (IL-8) (p=0.0006) secretion, while exogenous IL-23 significantly increased IL-6 (p=0.029), IL-22 (p=0.001), interleukin 17A (IL-17A) (p=0.0003) and interleukin 17F (IL-17F) (p=0.012) secretion. In ex vivo TA explants, IL-23 significantly increased gene expression of IL-8 (p=0.0001) and CCL-20 (p=0.027) and protein expression of IL-6 (p=0.002) and IL-8 (p=0.004). IL-12 (p=0.0005) and IL-23 (p<0.0001) stimulation increased the quantity of myofibroblast outgrowths from TABs. CONCLUSION: IL-12 and IL-23 play central and distinct roles in stimulating inflammatory and proliferative pathways relevant to GCA pathogenesis.


Subject(s)
Giant Cell Arteritis/immunology , Giant Cell Arteritis/pathology , Interleukin-12/immunology , Interleukin-23/immunology , Cell Proliferation/physiology , Humans , Inflammation/immunology , Inflammation/pathology , Temporal Arteries/pathology
12.
Semin Arthritis Rheum ; 48(3): 523-528, 2018 12.
Article in English | MEDLINE | ID: mdl-29776658

ABSTRACT

OBJECTIVES: Giant cell arteritis (GCA) is the most common form of systemic vasculitis. Glucocorticoids are an effective treatment but have significant adverse events and relapses are common. Interleukins 12 (IL-12) and 23 (IL-23) stimulate TH1 and TH17 responses and are implicated in the pathogenesis of GCA. The aim of this study was to evaluate the efficacy and safety of IL-12/23 blockade with ustekinumab in GCA. METHODS: We performed a prospective open label study of ustekinumab in patients with refractory GCA. Ustekinumab 90mg was administered subcutaneously every 12 weeks. The primary outcome was the comparison of the median glucocorticoid dose prior to commencement of ustekinumab and at 52 weeks. Secondary outcomes included physician assessed relapse, acute phase reactants, and imaging assessment of large vessel vasculitis (LVV). RESULTS: Twenty-five GCA patients received ustekinumab. All patients had failed to taper glucocorticoids despite addition of a median of 1 other immunosuppressive agent. At week 52, median (IQR) daily prednisolone dose decreased from 20 (15, 25)mg to 5 (2.5, 5)mg (p < 0.001). Six patients (24%) stopped prednisolone completely. No patient experienced a relapse of GCA while receiving ustekinumab. Median (IQR) CRP decreased significantly from 12.9 (5.3, 42) to 6 (2.6, 12.5)mg/L (p = 0.006). CT angiography demonstrated improvement of LVV in all patients studied. No unexpected adverse events were observed with ustekinumab. CONCLUSIONS: Ustekinumab may be effective for the treatment of GCA and warrants further assessment in a randomized controlled trial.


Subject(s)
Giant Cell Arteritis/drug therapy , Glucocorticoids/therapeutic use , Immunosuppressive Agents/therapeutic use , Prednisolone/therapeutic use , Ustekinumab/therapeutic use , Aged , Drug Administration Schedule , Drug Therapy, Combination , Female , Humans , Male , Middle Aged , Treatment Outcome
13.
Am J Hum Genet ; 100(1): 64-74, 2017 Jan 05.
Article in English | MEDLINE | ID: mdl-28041642

ABSTRACT

Giant cell arteritis (GCA) is the most common form of vasculitis in individuals older than 50 years in Western countries. To shed light onto the genetic background influencing susceptibility for GCA, we performed a genome-wide association screening in a well-powered study cohort. After imputation, 1,844,133 genetic variants were analyzed in 2,134 case subjects and 9,125 unaffected individuals from ten independent populations of European ancestry. Our data confirmed HLA class II as the strongest associated region (independent signals: rs9268905, p = 1.94 × 10-54, per-allele OR = 1.79; and rs9275592, p = 1.14 × 10-40, OR = 2.08). Additionally, PLG and P4HA2 were identified as GCA risk genes at the genome-wide level of significance (rs4252134, p = 1.23 × 10-10, OR = 1.28; and rs128738, p = 4.60 × 10-9, OR = 1.32, respectively). Interestingly, we observed that the association peaks overlapped with different regulatory elements related to cell types and tissues involved in the pathophysiology of GCA. PLG and P4HA2 are involved in vascular remodelling and angiogenesis, suggesting a high relevance of these processes for the pathogenic mechanisms underlying this type of vasculitis.


Subject(s)
Alleles , Genetic Predisposition to Disease/genetics , Genetic Variation , Genome-Wide Association Study , Giant Cell Arteritis/genetics , Plasminogen/genetics , Prolyl Hydroxylases/genetics , Aged , Aged, 80 and over , Cohort Studies , Europe/ethnology , Female , Humans , Male , Neovascularization, Physiologic , Polymorphism, Single Nucleotide/genetics , Risk
15.
Rheumatology (Oxford) ; 55(11): 1921-1931, 2016 11.
Article in English | MEDLINE | ID: mdl-26893518

ABSTRACT

GCA is a common primary systemic vasculitis that results in granulomatous inflammation of medium to large arteries. Both innate and adaptive immune mechanisms combine to drive intimal hyperplasia, luminal stenosis and ultimately occlusion. While the pathogenesis of GCA is incompletely understood, the activation of resident adventitial dendritic cells via toll like receptors (TLRs) appears to be a crucial inciting event. Here we explore the role of TLRs in the pathogenesis of GCA, including their effects on dendritic cell and T cell activation and recruitment, putative infectious triggers for GCA and the potential of TLR inhibition as a novel therapeutic strategy in GCA.


Subject(s)
Giant Cell Arteritis/etiology , Toll-Like Receptors/physiology , Dendritic Cells/physiology , Giant Cell Arteritis/therapy , Humans , Infections/physiopathology , Leukocytes, Mononuclear/metabolism , Lymphocyte Activation , Neovascularization, Pathologic/physiopathology , Polymorphism, Genetic/genetics , Signal Transduction/physiology , T-Lymphocytes/physiology , Toll-Like Receptor 4/genetics , Toll-Like Receptors/antagonists & inhibitors , Vascular Remodeling/physiology , Vasculitis/etiology
16.
Case Rep Oncol Med ; 2015: 934039, 2015.
Article in English | MEDLINE | ID: mdl-26558124

ABSTRACT

Malignant disease may be associated with a wide variety of musculoskeletal syndromes. Rarely the musculoskeletal system can be indirectly affected by paraneoplastic phenomena, such as carcinomatous polyarthritis (CP). The differential diagnosis for CP is broad and is often a diagnosis of exclusion. CP often presents similarly to other forms of inflammatory arthritis, and a detailed history and physical examination can often distinguish CP from other more common causes of polyarticular arthritis. However serological tests such as rheumatoid factor (RF) and anti-citrullinated peptide (anti-CCP) antibody positivity, while rare, can be misleading. Clinical awareness and suspicion are paramount in achieving an accurate diagnosis and early detection of an occult neoplasm is critical for prompt management and therapy. We report two cases presenting with this unique clinical phenotype associated with paraneoplastic polyarthropathy and review the literature.

17.
World J Clin Cases ; 3(6): 484-94, 2015 Jun 16.
Article in English | MEDLINE | ID: mdl-26090367

ABSTRACT

Glucocorticoids remain the cornerstone of medical therapy in giant cell arteritis (GCA) and should be started immediately to prevent severe consequences of the disease, such as blindness. However, glucocorticoid therapy leads to significant toxicity in over 80% of the patients. Various steroid-sparing agents have been tried, but robust scientific evidence of their efficacy and safety is still lacking. Tocilizumab, a monoclonal IL-6 receptor blocker, has shown promising results in a number of case series and is now being tested in a multi-centre randomized controlled trial. Other targeted treatments, such as the use of abatacept, are also now under investigation in GCA. The need for surgical treatment is rare and should ideally be performed in a quiescent phase of the disease. Not all patients follow the same course, but there are no valid biomarkers to assess therapy response. Monitoring of disease progress still relies on assessing clinical features and measuring inflammatory markers (C-reactive protein and erythrocyte sedimentation rate). Imaging techniques (e.g., ultrasound) are clearly important screening tools for aortic aneurysms and assessing patients with large-vessel involvement, but may also have an important role as biomarkers of disease activity over time or in response to therapy. Although GCA is the most common form of primary vasculitis, the optimal strategies for treatment and monitoring remain uncertain.

18.
Arthritis Rheumatol ; 67(9): 2447-56, 2015 Sep.
Article in English | MEDLINE | ID: mdl-26016600

ABSTRACT

OBJECTIVE: Giant cell arteritis (GCA) is pathologically characterized by dysfunctional angiogenesis and inflammatory cell infiltration. Acute-phase serum amyloid A (A-SAA) is an acute-phase reactant, but is also produced at sites of inflammation and may contribute to vascular inflammation in atherosclerosis. This study was undertaken to examine the effect of A-SAA on proinflammatory pathways and angiogenesis in GCA, using a novel ex vivo temporal artery tissue explant model. METHODS: Serum A-SAA levels were measured by enzyme-linked immunosorbent assay (ELISA). Temporal artery explants and peripheral blood mononuclear cell (PBMC) cultures were established from patients with GCA. Temporal artery explant morphology, viability, and spontaneous release of proinflammatory mediators following 24-hour culture were assessed by hematoxylin and eosin, calcein viability staining, and ELISA. Temporal artery explants and PBMC cultures were stimulated with A-SAA (10 µg/ml), and interleukin-6 (IL-6), IL-8, vascular endothelial growth factor, Ang2, and matrix metalloproteinase 2 (MMP-2)/MMP-9 were quantified by ELISA and gelatin zymography. The effect of conditioned medium from temporal artery explants on angiogenesis was assessed using endothelial cell Matrigel tube-formation assays. Temporal artery explants were also embedded in Matrigel, and myofibroblast outgrowth was assessed. RESULTS: Serum A-SAA levels were significantly higher in GCA patients versus healthy controls (P < 0.0001). Intact tissue morphology, cell viability, and spontaneous cytokine secretion were demonstrated in temporal artery explants. A-SAA treatment induced a significant increase in the levels of IL-6 and IL-8 from temporal artery explants (P < 0.05) and IL-8 from PBMCs (P < 0.05) compared to basal conditions. Conditioned medium from A-SAA-treated explants significantly induced angiogenic tube formation (P < 0.05 versus basal controls). Finally, A-SAA induced myofibroblast outgrowth and MMP-9 activation. CONCLUSION: Our findings demonstrate a functional role for A-SAA in regulating temporal artery inflammation, angiogenesis, and invasion, all key processes in the pathogenesis of GCA.


Subject(s)
Giant Cell Arteritis/immunology , Myofibroblasts/drug effects , Neovascularization, Pathologic/immunology , Serum Amyloid A Protein/pharmacology , Temporal Arteries/drug effects , Acute-Phase Proteins/immunology , Acute-Phase Proteins/pharmacology , Aged , Aged, 80 and over , Cells, Cultured , Female , Giant Cell Arteritis/metabolism , Humans , In Vitro Techniques , Inflammation/immunology , Interleukin-6/immunology , Interleukin-8/drug effects , Interleukin-8/immunology , Leukocytes, Mononuclear , Male , Matrix Metalloproteinase 2/drug effects , Matrix Metalloproteinase 2/immunology , Matrix Metalloproteinase 9/drug effects , Matrix Metalloproteinase 9/immunology , Middle Aged , Serum Amyloid A Protein/immunology , Temporal Arteries/immunology , Vascular Endothelial Growth Factor A/drug effects , Vascular Endothelial Growth Factor A/immunology , Vesicular Transport Proteins/drug effects , Vesicular Transport Proteins/immunology
19.
Arthritis Rheum ; 64(5): 1601-9, 2012 May.
Article in English | MEDLINE | ID: mdl-22127978

ABSTRACT

OBJECTIVE: To examine the role of interferon regulatory factor 3 (IRF-3) in the regulation of interleukin-23 (IL-23) production in patients with systemic lupus erythematosus (SLE). METHODS: Bone marrow-derived macrophages were isolated from both wild-type and IRF3(-/-) C57BL/6 mice. These cells were stimulated with the Toll-like receptor 3 (TLR-3) agonist poly(I-C), and IL-23p19 cytokine levels were analyzed by enzyme-linked immunosorbent assay. IRF-3 binding to the IL-23p19 gene promoter region in monocytes from patients with SLE and healthy control subjects was analyzed by chromatin immunoprecipitation (ChIP) assay. Luciferase reporter gene assays were performed to identify key drivers of IL-23p19 promoter activity. TANK-binding kinase 1 (TBK-1) protein levels were determined by Western blotting. RESULTS: ChIP assays demonstrated that IRF-3 was stably bound to the human IL-23p19 promoter in monocytes; this association increased following TLR-3 stimulation. Patients with SLE demonstrated increased levels of IRF-3 bound to the IL-23p19 promoter compared with control subjects, which correlated with enhanced IL-23p19 production in monocytes from patients with SLE. Investigations of the TLR-3-driven responses in monocytes from patients with SLE revealed that TBK-1, which is critical for regulating IRF-3 activity, was hyperactivated in both resting and TLR-3-stimulated cells. CONCLUSION: Our results demonstrate for the first time that patients with SLE display enhanced IL-23p19 expression as a result of hyperactivation of TBK-1, resulting in increased binding of IRF-3 to the promoter. These findings provide novel insights into the molecular pathogenesis of SLE and the potential role for TLR-3 in driving this response.


Subject(s)
Interferon Regulatory Factor-3/metabolism , Interleukin-23 Subunit p19/metabolism , Lupus Erythematosus, Systemic/metabolism , Animals , Bone Marrow Cells/drug effects , Bone Marrow Cells/metabolism , Chromatin Immunoprecipitation , Disease Models, Animal , Female , Gene Expression Regulation , Humans , Interferon Regulatory Factor-3/genetics , Interleukin-23 Subunit p19/genetics , Macrophages/drug effects , Macrophages/metabolism , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Monocytes/metabolism , Poly I-C/pharmacology , Protein Array Analysis/methods , Protein Binding , Protein Serine-Threonine Kinases/pharmacology , Toll-Like Receptor 3/immunology
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