ABSTRACT
OBJECTIVES: Myositis autoantibodies (MAs) were traditionally used as a diagnostic biomarker for idiopathic inflammatory myopathy (IIM). Its clinical utility had recently expanded to include interstitial lung disease (ILD) diagnosis. Depending on the patient cohort, MAs false positives can be common. Correlation between ANA indirect immunofluorescent (IIF) pattern and MAs may improve its positive predictive value (PPV). The aim of our study was to determine the PPV of MAs in IIM and ILD in a real-world patient cohort. We also assessed whether concordance between MAs and ANA IIF pattern can improve the PPV of positive MA results. METHODS: Patients with positive MAs and corresponding ANA IIF pattern were identified from Sutherland Centre of Immunology, New South Wales Health Pathology, Australia. The corresponding health records were reviewed to identify each patient's primary diagnosis. χ2 test was used to compare the PPV between MA-ANA concordant and discordant groups. RESULTS: Between January 2016 and July 2019, 118 patients were positive for at least one MA (mean age 66.7 years, 55% female). The most frequently detected autoantibodies were Ro52, anti-synthetase antibodies and PM-Scl. The PPV of MAs for IIM or ILD was 47.4%. The overall concordance rate of MAs and ANA IIF pattern was 70.2%. Patients with concordant MA-ANA results were more likely to have true clinical disease (64.1% vs 17.8%, P <0.001). CONCLUSION: Myositis autoantibodies have a low PPV for IIM and ILD in a real-world patient cohort. A positive concordance with ANA IIF pattern can improve MA test accuracy.
Subject(s)
Lung Diseases, Interstitial , Myositis , Aged , Antibodies, Antinuclear , Australia , Autoantibodies , Female , Humans , Male , Myositis/diagnosisABSTRACT
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.
Subject(s)
Arthritis, Rheumatoid , Epstein-Barr Virus Infections , Lymphoma, Large B-Cell, Diffuse , Lymphoproliferative Disorders , Humans , Epstein-Barr Virus Infections/complications , Epstein-Barr Virus Infections/drug therapy , Methotrexate/adverse effects , Herpesvirus 4, Human , Abatacept/therapeutic use , Arthritis, Rheumatoid/complications , Arthritis, Rheumatoid/drug therapy , Lymphoproliferative Disorders/chemically induced , Lymphoproliferative Disorders/complications , Lymphoproliferative Disorders/epidemiology , Immunosuppressive Agents/adverse effectsABSTRACT
OBJECTIVES: To report the efficacy and tolerability of mycophenolate mofetil (MMF) and azathioprine (AZA) in the management of systemic sclerosis-associated interstitial lung disease (SSc-ILD). METHODS: Patients in the Australian Scleroderma Cohort Study treated with at least 3 months of MMF or AZA for SSc-ILD confirmed on high resolution computed tomography (HRCT) chest were identified and their pulmonary function tests (PFTs) retrieved. Individuals with available results for T-1 (12 months prior to treatment commencement), T0 (date of treatment commencement) and at least one subsequent time point were included in the drug efficacy analysis. The Wilcoxon signed-rank test was used to compare absolute FVC at T1, T0, 12 months (T1), 24 months (T2) and 36 months (T3). Analysis of drug tolerability included all identified patients treated with MMF or AZA. RESULTS: 18/22 patients treated with MMF and 29/49 treated with AZA had adequate PFTs for inclusion in the drug efficacy analysis. Median absolute FVC at T1 for MMF treatment was 2.50L, declining to 2.12L at T0 (p=0.02). Following MMF therapy, FVC results were stable at T1 (2.13L, p=0.86), T2 (2.17L, p=0.65) and T3 (2.25L, p=0.78). In the AZA group, a statistically significant decline did not occur prior to treatment, however FVC results remained stable at T1, T2 and T3.Adverse events leading to early discontinuation (<12 months treatment) were less common in the MMF group (4/22 vs. 13/49). Gastrointestinal complications were the main cause of discontinuation in both groups. CONCLUSIONS: In patients with SSc-ILD with declining pulmonary function, MMF therapy was associated with stability for up to 36 months. Early adverse events leading to discontinuation occurred less frequently in patients treated with MMF than in AZA treated patients.
Subject(s)
Immunosuppressive Agents/therapeutic use , Lung Diseases, Interstitial/drug therapy , Lung/drug effects , Mycophenolic Acid/therapeutic use , Scleroderma, Systemic/drug therapy , Adult , Aged , Australia , Azathioprine/therapeutic use , Databases, Factual , Drug Therapy, Combination , Female , Humans , Immunosuppressive Agents/adverse effects , Longitudinal Studies , Lung/physiopathology , Lung Diseases, Interstitial/diagnosis , Lung Diseases, Interstitial/etiology , Lung Diseases, Interstitial/physiopathology , Male , Middle Aged , Mycophenolic Acid/adverse effects , Respiratory Function Tests , Retrospective Studies , Scleroderma, Systemic/complications , Scleroderma, Systemic/diagnosis , Time Factors , Tomography, X-Ray Computed , Treatment OutcomeABSTRACT
INTRODUCTION AND HYPOTHESIS: The classic triad of dry eyes, mouth and vagina is known to most gynaecologists as pathognomonic of Sjögren's syndrome, but rheumatologists seldom consider vaginal symptoms. Our hypothesis was that women with Sjögren's syndrome would have an increased likelihood of postoperative voiding dysfunction, severe vaginal stenosis or poor response to anticholinergics compared with the general urogynaecology patient. METHODS: All patients with Sjögren's syndrome were prospectively recorded from July 2007 to June 2015. Presenting complaint, pelvic examination findings, previous/subsequent pelvic surgery, voiding dysfunction and response to anticholinergics were noted. The denominator, all new urogynaecology patients, was prospectively recorded. RESULTS: Fifteen patients were identified over 8 years (0.5 % of 2794 new presentations). Of the seven patients who had previously undergone surgery elsewhere, all had demonstrable pelvic tissue fibrosis; five had such severe fibrosis that no speculum could be passed. Anticholinergic medications were completely intolerable in 10/11 (91 %) women, and severe postoperative voiding dysfunction occurred in 6/9 (67 %) women. Only 2/15 (13 %) women were unaffected by fibrosis, postoperative voiding dysfunction or intolerance to anticholinergics. CONCLUSIONS: This audit demonstrates a substantial risk of vaginal stenosis, postoperative voiding dysfunction or severe intolerance to anticholinergics in women with Sjögren's syndrome.
Subject(s)
Pelvic Floor Disorders/etiology , Pelvic Floor/surgery , Postoperative Complications/etiology , Sjogren's Syndrome/complications , Aged , Cholinergic Antagonists/adverse effects , Constriction, Pathologic/etiology , Drug Tolerance , Female , Humans , Medical Audit , Middle Aged , Pelvic Floor/physiopathology , Pelvic Floor Disorders/therapy , Prospective Studies , Risk Factors , Sjogren's Syndrome/physiopathology , Urination Disorders/etiology , Vagina/surgeryABSTRACT
OBJECTIVE: Beta-2-glycoprotein I (ß2 GPI) constitutes the major autoantigen in the antiphospholipid syndrome (APS), a common acquired cause of arterial and venous thrombosis. We recently described the novel observation that ß2 GPI may exist in healthy individuals in a free thiol (biochemically reduced) form. The present study was undertaken to quantify the levels of total, reduced, and posttranslationally modified oxidized ß2 GPI in APS patients compared to various control groups. METHODS: In a retrospective multicenter analysis, the proportion of ß2 GPI with free thiols in serum from healthy volunteers was quantified. Assays for measurement of reduced as well as total circulating ß2 GPI were developed and tested in the following groups: APS (with thrombosis) (n=139), autoimmune disease with or without persistent antiphospholipid antibodies (aPL) but without APS (n=188), vascular thrombosis without APS or aPL (n=38), and healthy volunteers (n=91). RESULTS: Total ß2 GPI was significantly elevated in patients with APS (median 216.2 µg/ml [interquartile range 173.3-263.8]) as compared to healthy subjects (median 178.4 µg/ml [interquartile range 149.4-227.5] [P<0.0002]) or control patients with autoimmune disease or vascular thrombosis (both P<0.0001). The proportion of total ß2 GPI in an oxidized form (i.e., lacking free thiols) was significantly greater in the APS group than in each of the 3 control groups (all P<0.0001). CONCLUSION: This large retrospective multicenter study shows that posttranslational modification of ß2 GPI via thiol-exchange reactions is a highly specific phenomenon in the setting of APS thrombosis. Quantification of posttranslational modifications of ß2 GPI in conjunction with standard laboratory tests for APS may offer the potential to more accurately predict the risk of occurrence of a thrombotic event in the setting of APS.
Subject(s)
Antibodies, Antiphospholipid/blood , Antiphospholipid Syndrome/blood , Thrombosis/etiology , beta 2-Glycoprotein I/blood , beta 2-Glycoprotein I/immunology , Adult , Antibodies, Antiphospholipid/immunology , Antiphospholipid Syndrome/immunology , Female , Humans , Male , Middle Aged , Retrospective Studies , Thrombosis/blood , Thrombosis/immunologyABSTRACT
Increased oxidative stress is a hallmark of the autoimmune disease systemic lupus erythematosus (SLE). This study compares serum protein oxidation levels in SLE patients without and with renal involvement (lupus nephritis); the latter have a significantly poorer prognosis. Similar increases in protein carbonyls and decreases in protein thiols were observed in both SLE groups compared to controls. Protein carbonyl distribution, determined by Western blotting of 2D gels, was similar in both SLE groups, suggesting factors other than oxidation also play a role in SLE complications. 2D electrophoresis examined the serum proteome further. Six proteins were significantly decreases in non-renal SLE patients compared to controls; five were identified by mass spectrometry, including one isoform of pro-atherogenic apoCIII. Total apoCIII levels (assessed by ELISA) in lupus nephritis patients were significantly elevated compared to controls or non-renal SLE patients. Thus, levels of oxidized proteins and apoCIII may be useful biomarkers in SLE studies.
Subject(s)
Apolipoprotein C-III/blood , Blood Proteins/metabolism , Lupus Erythematosus, Systemic/blood , Nephritis/blood , Adult , Apolipoprotein C-III/isolation & purification , Biomarkers/blood , Blood Proteins/isolation & purification , Electrophoresis, Gel, Two-Dimensional , Enzyme-Linked Immunosorbent Assay , Female , Humans , Lupus Erythematosus, Systemic/classification , Lupus Erythematosus, Systemic/complications , Lupus Erythematosus, Systemic/physiopathology , Male , Middle Aged , Nephritis/etiology , Oxidation-Reduction , ProteomeSubject(s)
Chest Pain/etiology , Dermatomyositis/diagnosis , Hydroxymethylglutaryl-CoA Reductase Inhibitors/adverse effects , Troponin/blood , Dermatomyositis/complications , Dermatomyositis/pathology , Diagnosis, Differential , Emergency Service, Hospital , Humans , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Male , Middle Aged , Rosuvastatin Calcium/adverse effects , Rosuvastatin Calcium/therapeutic useABSTRACT
To enable clinicians to use autoantibody tests sensibly and economically, laboratories providing the test service have a responsibility to supply the test 'specifications'. This should include information about the test's validity and reliability, its normal range or range within a control population, its sensitivity and its specificity for different conditions against both control subjects and those with disorders which need to be distinguished by the test. This information will permit the development of predictive values, or better, of likelihood ratios which can then be used to generate clinically useful post-test probabilities. To date, autoantibody tests have been used to advantage by those skilled in their interpretation but often poorly by those less familiar with the area. It is appropriate now to demystify these tests by underpinning their clinical use with good operational data.
Subject(s)
Autoantibodies/analysis , Autoimmune Diseases/diagnosis , Immunoassay/statistics & numerical data , Autoantibodies/blood , Autoimmune Diseases/immunology , Humans , Immunoassay/standards , Likelihood Functions , Predictive Value of Tests , Reproducibility of Results , Sensitivity and SpecificityABSTRACT
AIMS: To assess the intra-assay (intra-run) and inter-assay (inter-run) variation of commercial and in-house IgG and IgM anti-cardiolipin antibody (aCL) assays/kits, and to determine an appropriate maximum value for inclusion in consensus guidelines. METHODS: Frozen aliquots of two patient specimens and one commercial control were sent to nine laboratories for the evaluation of eight commercial kits and one in-house assay. Intra-assay and inter-assay evaluations were performed with all three samples for IgG aCL, and one patient specimen for IgM aCL. RESULTS: The IgG and IgM aCL values varied considerably between the nine assays/kits. The majority of assays/kits demonstrated less than 20% intra-assay and inter-assay variation, with lower intra-assay and inter-assay variation observed with the commercial control. Single calibrator assays were not consistently associated with higher inter-assay variation than multi-point calibrator assays. CONCLUSIONS: An inter-assay coefficient of variation of 20% was determined to be an appropriate maximum value for inclusion in the Australasian aCL Working Party consensus guidelines. Improved standardisation between different assay/kits is still required.
Subject(s)
Antibodies, Anticardiolipin/analysis , Clinical Laboratory Techniques/standards , Laboratories/standards , Quality Assurance, Health Care , Reagent Kits, Diagnostic/standards , Australia , Consensus , Enzyme-Linked Immunosorbent Assay/standards , Humans , Immunoglobulin G/analysis , Immunoglobulin M/analysis , Reproducibility of ResultsABSTRACT
UNLABELLED: Consensus guidelines on anti-cardiolipin antibody (aCL) testing have been developed to help minimise laboratory variation in the performance and reporting of aCL assays. These guidelines include minimum, optimum and optional recommendations for the following aspects of aCL testing and reporting: (1) isotype of aCL tested; (2) specimen type; (3) controls and assay precision; (4) calibrators; (5) patient samples; (6) rheumatoid factors and IgM aCL testing; (7) reporting of results; (8) cut-off values; and (9) interpretative comments. ABBREVIATIONS: aCL, anti-cardiolipin antibodies; APS, anti-phospholipid antibody syndrome; ASCIA, Australasian Society of Clinical Immunology and Allergy; ASTH, Australasian Society of Thrombosis and Haemostasis; beta2-GPI=beta2-glycoprotein I; ELISA, enzyme-linked immunosorbent assay; NCCLS, National Committee for Clinical Laboratory Standards; HSANZ, Haematology Society of Australia and New Zealand; QAP, Quality Assurance Program; RCPA, Royal College of Pathologists of Australasia; %CV, inter-assay inter-run coefficient of variation.
Subject(s)
Antibodies, Anticardiolipin/blood , Enzyme-Linked Immunosorbent Assay/standards , Quality Assurance, Health Care/standards , Australia , Enzyme-Linked Immunosorbent Assay/methods , Humans , New Zealand , Reproducibility of Results , Sensitivity and SpecificityABSTRACT
Early diagnosis and treatment of rheumatoid arthritis (RA) is necessary to prevent joint damage and long-term disability. High rates of false-negative and false-positive results of the rheumatoid factor (RF) test make it generally unhelpful in the early diagnosis of RA. A new clinical test for RA--the anti-citrullinated peptide antibody (ACPA) test--is now widely available in Australia. Owing to its high specificity (95%), a positive ACPA test result usually confirms a diagnosis of RA in a patient with undifferentiated inflammatory arthritis. The superior specificity of the ACPA test provides an argument for it to replace the RF test in the primary care setting. Performing both tests adds little to the use of the ACPA test alone. An early diagnostic opinion from a rheumatologist is still recommended, as the ACPA and RF tests frequently return negative results in early RA.
Subject(s)
Arthritis, Rheumatoid/immunology , Autoantibodies/blood , Peptides, Cyclic/immunology , Rheumatoid Factor/blood , Arthritis, Rheumatoid/blood , Arthritis, Rheumatoid/diagnosis , Diagnosis, Differential , Enzyme-Linked Immunosorbent Assay , Humans , Sensitivity and SpecificityABSTRACT
Serum protein oxidation levels in people with the autoimmune disease systemic lupus erythematosus (SLE) have previously been shown to (a) be elevated at a single time point and (b) correlate with disease activity. This study investigates whether this elevation is a chronic phenomenon, by analysis of multiple serum samples collected from 21 SLE patients and nine controls over a period of up to 38 months. Protein thiols were chronically decreased in SLE patients with stable or variable disease activity compared to controls, whilst protein-bound carbonyls and glycine were chronically increased. 2D-gel analysis of carbonyl distribution showed albumin and immunoglobulins to be particularly affected. In SLE patients with stable disease activity, higher long-term protein oxidation correlated with higher long-term disease activity. SLE patients with variable disease activity exhibited varying correlations between protein oxidation and disease activity markers. These results further support a role for oxidative stress in the pathogenesis of SLE.
Subject(s)
Blood Proteins/metabolism , Lupus Erythematosus, Systemic/blood , Adult , Blotting, Western , Case-Control Studies , Cohort Studies , Disease Progression , Electrophoresis, Gel, Two-Dimensional , Female , Humans , Male , Middle Aged , Oxidation-Reduction , Oxidative Stress/physiology , Protein Binding , Severity of Illness IndexABSTRACT
A 48-year-old woman presented with acute unilateral ischaemia of the left hand. She had a background of chronic peripheral neuropathic pain, palpitations, anaemia and an episode of superficial thrombophlebitis. Physical examination revealed non-blanching purple discoloration of her left fingers and her left thumb, index finger and thenar eminance appeared ischaemic. Digital subtraction angiography of the left hand demonstrated reduced flow. Skin punch biopsy histology was unremarkable. The diagnosis of Fabry disease was made on urine lipid profile analysis and confirmed by reduced peripheral blood leukocyte alpha-galactosidase A activity.
Subject(s)
Fabry Disease/diagnosis , Hand/blood supply , Ischemia/diagnosis , Paresthesia/diagnosis , Diagnosis, Differential , Fabry Disease/blood , Fabry Disease/pathology , Fabry Disease/urine , Female , Humans , Ischemia/pathology , Leukocytes/enzymology , Lipids/urine , Middle Aged , Paresthesia/pathology , alpha-Galactosidase/bloodABSTRACT
OBJECTIVE: To examine protein oxidation in systemic lupus erythematosus (SLE) and to correlate levels of protein oxidation products with disease activity. METHODS: Serum was collected from SLE patients and healthy control subjects. Protein-bound carbonyls and the pro-oxidant enzyme myeloperoxidase (MPO) were quantified by enzyme-linked immunosorbent assay. Protein thiols were quantified using 5,5'-dithionitrobenzoic acid. Protein-bound amino acids and methionine, tyrosine, and phenylalanine oxidation products were quantified by acid hydrolysis and high-performance liquid chromatography. Disease activity was assessed by the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI). Levels of anti-double-stranded DNA (anti-dsDNA) antibodies were measured by radioimmunoassay. RESULTS: Compared with control subjects, SLE patients exhibited elevated levels of protein carbonyls (0.108 +/- 0.078 versus 0.064 +/- 0.028 nmoles/mg of protein; P = 0.046), decreased levels of protein thiols (3.9 +/- 1.1 versus 4.9 +/- 0.7 nmoles/mg of protein; P = 0.003), decreased levels of protein-bound methionine (P = 0.0007), and increased levels of protein-bound methionine sulfoxide (P = 0.0043) and 3-nitrotyrosine (P = 0.0477). SLE patients with high SLEDAI scores or elevated anti-dsDNA antibody levels exhibited increased oxidation compared with patients with low SLEDAI scores or low antibody levels. Serum MPO levels were decreased in SLE patients (P = 0.03), suggesting that this enzyme is not responsible for the enhanced protein oxidation. CONCLUSION: We found elevated levels of multiple markers of protein oxidation in sera from SLE patients compared with controls, and these levels correlated with disease activity. The findings suggest that protein oxidation may play a role in the pathogenesis of chronic organ damage in SLE.