Systemic Autoimmune Rheumatic Diseases Research Articles

Interstitial lung involvement in rheumatoid arthritis

Rheumatoid arthritis (RA) is a systemic autoimmune rheumatic disease of unknown etiology, characterized by chronic erosive arthritis and extraarticular manifestations. Pulmonary involvement is one of the common extraarticular manifestations of RA and may show itself as bronchial tree lesions, rheumatoid nodules, Caplan's syndrome, and lesions in the pleura or pulmonary interstitium (interstitial lung involvement (ILI)). High-resolution computed tomography allows the diagnosis of ILI in RA in nearly 70% of cases although the incidence of ILI may be lower (4 to 30%) depending on diagnostic methods and patient selection criteria. There are several histopathological types of ILI, the differential diagnosis of which can be troublesome. Usual interstitial pneumonia (UIP) and nonspecific interstitial pneumonia are major types of RA-associated ILI. UIP-pattern ILI has a more severe course than ILI with other histological patterns. The clinical presentation of ILI may be complicated by the likely toxic effect of a number of disease-modifying antirheumatic drugs (DMARDs) used to treat RA, such as methotrexate and leflunomide, and biological agents (BAs), tumor necrosis factor- α (TNF- α ) inhibitors. The pathogenesis of pulmonary involvement in RA and the role of synthetic DMARDs and BAs in the development of ILI call for further investigations. An extraarticular manifestation, such as ILI, affects the choice of treatment policy in patients with RA. The relevance of a study of ILI is beyond question. The paper discusses the state-of-the-art of investigations in this area.

How to investigate multisystem disease.

The investigation of the patient with possible systemic autoimmune rheumatic disease is potentially one of the most challenging areas of rheumatology as the differential diagnosis is potentially very broad. The investigative approach should not only be directed at confirming the diagnosis of an autoimmune rheumatic disease but also at excluding as best as possible the major alternative diagnoses of malignancy and infection. A systematic approach should yield a positive diagnosis in the majority of cases based on excluding infection by appropriate cultures and serology, malignancy using imaging including 18-fluorodeoxyglucose positron emission tomography/computerized tomography (FDG PET/CT). The most important part of the assessment is the history, in particular covering systems that may not previously been assessed such as ears, nose, throat or eyes. The clue to the diagnosis of an autoimmune rheumatic disease often lies in detecting the multisystem nature of the condition and the cumulative effects of multiorgan involvement. Investigation may therefore need to cover different systems. Although stratified approaches have been described, they have not been subjected to a detailed investigation as to their effectiveness.

Clinical performance evaluation of a novel, automated chemiluminescent immunoassay, QUANTA Flash CTD Screen Plus.

The QUANTA Flash(®) CTD Screen Plus is a chemiluminescent immunoassay (CIA) for the detection of the major antinuclear antibodies (ANA) on the BIO-FLASH(®) platform. NOVA View(®) is an automated fluorescence microscope that acquires digital images of indirect immunofluorescent assay (IFA) slides. Our goal was to evaluate the clinical performance of the two automated systems and compare their performance to that of traditional IFA. Sera from patients with systemic autoimmune rheumatic diseases (SARD, n = 178), along with disease and healthy controls (n = 204), were tested with the CTD CIA and with NOVA Lite(®) HEp-2 ANA, using both the manual method of reading the IFA slides and the NOVA View instrument. The CTD CIA showed 78.1% sensitivity for SARD, coupled with 94.1% specificity. Manual IFA and NOVA View showed somewhat higher sensitivity (81.5 and 84.8% in SARD, respectively), but significantly lower specificity (79.4 and 64.7%, respectively). Both automated systems displayed somewhat different performance, due to the different principals of ANA detection: IFA with NOVA View digital image interpretation had higher sensitivity, while the CTD CIA showed higher specificity. With the added benefits of full automation, the new CTD CIA is an attractive alternative to traditional ANA screening.

Abnormal antibodies: what do you do?

Systemic autoimmune rheumatic diseases encompass a vast array of autoantibodies which are very useful to confirm a suspected diagnosis. This article gives an overview of the most common autoantibodies, how they are tested and the significance of a positive test in a clinical context.

The prevalence of systemic autoimmune rheumatic diseases in Canadian pediatric populations: administrative database estimates.

To estimate systemic autoimmune rheumatic disease (SARD) prevalence using administrative data for pediatric populations in four Canadian provinces. Physician billing claims and inpatient hospitalizations from Alberta, Manitoba, Quebec, and Saskatchewan were used to define cases aged ≤18 years with a SARD diagnosis code in: one or more hospitalization, two or more physician visits within 2 years and at least 2 months apart, or one or more physician visit to a rheumatologist. Estimates ranged from 15.9/100,000 in Quebec [95% confidence interval (95% CI) 14.1, 18.0] to 23.0/100,000 in Manitoba (95% CI 17.9, 29.2). SARDs were more common in females than in males across all provinces. There was a slightly higher prevalence among those living in urban compared to rural areas of Alberta (rate difference 14.4, 95% CI 8.6, 20.1) and Saskatchewan (rate difference 13.8, 95% CI 1.0, 26.6). Our results provide population-based prevalence estimates of pediatric SARDs in four Canadian provinces.

Vaccinations Should Be Part of Treatment Plans for Patients on Biologic Therapies

Systemic autoimmune rheumatic diseases often are associated with infectious complications, and the confusing array of new biologic therapies and

The challenge of identification of autoantibodies specific to systemic autoimmune rheumatic diseases in high throughput operation: Proposal of reliable and feasible strategies

BackgroundAutoantibodies to extractable nuclear antigens (ENA) are good biomarkers for systemic autoimmune rheumatic diseases (SARD), but no one assay for the detection of these antibodies provides satisfactory sensitivity and positive predictive value (PPV). Here we evaluate current assays and propose novel strategies to detect anti-ENA antibodies. MethodsDiagnostic performance of double immunodiffusion (DID) and several enzyme immunoassays (EIA) for the detection of anti-ENA autoantibodies was determined using samples from 144 patients with a previous clinical diagnosis of SARD and 121 non-autoimmune individuals. A 2-step assay combining EIA and DID was developed and tested on 16,458 serum samples. ResultsEIA was more sensitive than DID for all anti-ENA antibodies, but yielded lower PPV (mean=66%) than DID (mean=96%) and a higher percentage of unexpected positive results. ROC-curve guided cut-off adjustments improved PPV for most EIA kits. Using the 2-step assay, over 80% of the samples were screened out by the first step (EIA), with results available within 24h, leaving only about 20% to be confirmed by DID. 2.9% of the 16,485 samples were found to be positive. ConclusionsA 2-step assay combining the speed and potential for automation of EIA with the high specificity and PPV of DID allows efficient and reliable detection of anti-ENA antibodies. Alternatively, improved PPV can be achieved by adjusting cut-off values for EIA assay results.

AB1027 Diagnostic Accuracy of Automated Determination of Antinuclear Antibodies (ANA) by Indirect REAction of Immunofluorescence on Human Hep-2 Cells (IIF-HEP-2) and Enzyme-Linked Immunosorbent Assay (ELISA) for Diagnosis of Systemic Lupus Erythematosus (SLE)

BackgroundANA – heterogeneous group of autoantibodies, reacting with the different components of nucleus and cytoplasm. ANA is main serological marker SLE and others systemic autoimmune rheumatic diseases (SARDs). The implementation...

Systemic Autoimmune Rheumatic Disease Prevalence in Canada: Updated Analyses Across 7 Provinces

To estimate systemic autoimmune rheumatic disease (SARD) prevalence across 7 Canadian provinces using population-based administrative data evaluating both regional variations and the effects of age and sex. Using provincial physician billing and hospitalization data, cases of SARD (systemic lupus erythematosus, scleroderma, primary Sjögren syndrome, polymyositis/dermatomyositis) were ascertained. Three case definitions (rheumatology billing, 2-code physician billing, and hospital diagnosis) were combined to derive a SARD prevalence estimate for each province, categorized by age, sex, and rural/urban status. A hierarchical Bayesian latent class regression model was fit to account for the imperfect sensitivity and specificity of each case definition. The model also provided sensitivity estimates of different case definition approaches. Prevalence estimates for overall SARD ranged between 2 and 5 cases per 1000 residents across provinces. Similar demographic trends were evident across provinces, with greater prevalence in women and in persons over 45 years old. SARD prevalence in women over 45 was close to 1%. Overall sensitivity was poor, but estimates for each of the 3 case definitions improved within older populations and were slightly higher for men compared to women. Our results are consistent with previous estimates and other North American findings, and provide results from coast to coast, as well as useful information about the degree of regional and demographic variations that can be seen within a single country. Our work demonstrates the usefulness of using multiple data sources, adjusting for the error in each, and providing estimates of the sensitivity of different case definition approaches.

New laboratory markers for the management of rheumatoid arthritis patients.

Rheumatoid arthritis, the most prominent of systemic autoimmune rheumatic diseases, represents an important social health problem. Recent insights into the immunopathogenic mechanism of this complex and multiform illness might open new perspectives for a more appropriate laboratory approach. In this review we focus on the most relevant pathogenetic mechanism; indicating the laboratory biomarkers specifically linked to early diagnosis, prognosis, evolutive aspects of the disease, and therapeutic efficacy. Evidence based on laboratory medicine could provide the best outcome for patients.

Anti-hnRNP B1 (RA33) autoantibodies are associated with the clinical phenotype in Russian patients with rheumatoid arthritis and systemic sclerosis.

Heterogeneous nuclear ribonucleoproteins (hnRNPs) are potent autoantigenic targets in systemic autoimmune rheumatic diseases (SARD). Loss of tolerance to the RA33 complex consisting of hnRNP A2 and its alternatively spliced variants B1 and B2 has been the interest of rheumatologists. A novel ELISA for the detection of anti-hnRNP B1 autoantibodies has been developed to investigate the prevalence thereof in 397 patients with SARD, including patients with rheumatoid arthritis (RA), spondyloarthropathy (SPA), juvenile chronic arthritis, systemic lupus erythematosus (SLE), systemic sclerosis (SSc), and Sjögren's syndrome (SS), in comparison to 174 controls. Anti-hnRNP B1 autoantibodies were significantly more prevalent in patients with SARD than controls (47/397, 11.8% versus 2/174, 1.1%; P < 0.001). In particular, anti-hnRNP B1 were found more frequently in the disease cohorts than in the controls and were present in 24/165 (14.5%) patients with RA, 6/58 (10.3%) SPA, 11/65 (16.9%) SSc, and 4/50 (8.0%) SLE. In RA patients, anti-hnRNP B1 autoantibodies correlated significantly with C-reactive protein levels and erythrocyte sedimentation rate, while in patients with SSc it was associated with features of arterial wall stiffness and presence of hypertension. Anti-hnRNP B1 autoantibodies occur in SARD and seem to be correlated with distinct clinical characteristics in patients with RA and SSc.

Anti-nuclear antibodies in daily clinical practice: prevalence in primary, secondary, and tertiary care.

For the diagnosis of systemic autoimmune rheumatic diseases (SARD), patients are screened for anti-nuclear antibodies (ANA). ANA, as assessed by indirect immunofluorescence (IIF), have a poor specificity. This hampers interpretation of positive results in clinical settings with low pretest probability of SARD. We hypothesized that the utility of positive ANA IIF results increases from primary to tertiary care. We retrospectively determined ANA, anti-ENA, and anti-dsDNA antibody prevalence in patient cohorts from primary (n = 1453), secondary (n = 1621), and tertiary (n = 1168) care settings. Results reveal that from primary care to tertiary care, ANA prevalence increases (6.2, 10.8, and 16.0%, resp.). Moreover, in primary care low titres (70% versus 51% and 52% in secondary and tertiary care, resp.) are more frequent and anti-ENA/dsDNA reactivities are less prevalent (21% versus 39% in secondary care). Typically, in tertiary care the prevalence of anti-ENA/dsDNA reactivities (21%) is lower than expected. From this descriptive study we conclude that positive ANA IIF results are more prone to false interpretation in clinical settings with low pretest probabilities for SARD, as in primary care. Whether alternative approaches, that is, immunoadsorption of anti-DFS70 antibodies or implementation of anti-ENA screen assays, perform better, needs to be determined.

The spectrum of anti-chromatin/nucleosome autoantibodies: independent and interdependent biomarkers of disease.

Autoantibodies directed to chromatin components date back to the discovery of the LE cell and the LE cell phenomenon circa 1950, and subsequent evidence that major components of that reaction were chromatin components and histones in particular. Over time, immunoassays ranging from ELISA and line immunoassays to more modern bead-based assays incorporated histone and DNA mixtures, purified histones, and purified nucleosomes leading to a more thorough understanding of the genesis and pathogenetic relationships of antibodies to chromatin components in systemic lupus erythematosus and other autoimmune conditions. More recently, interest has focussed on other components of chromatin such as high mobility group (HMG) proteins both as targets of B cell responses and pro-inflammatory mediators. This review will focus on immunoassays that utilize chromatin components, their clinical relationships, and newer evidence implicating HMG proteins and DNA neutrophil extracellular traps (NETs) as important players in systemic autoimmune rheumatic diseases.

Current concepts and future directions for the assessment of autoantibodies to cellular antigens referred to as anti-nuclear antibodies.

The detection of autoantibodies that target intracellular antigens, commonly termed anti-nuclear antibodies (ANA), is a serological hallmark in the diagnosis of systemic autoimmune rheumatic diseases (SARD). Different methods are available for detection of ANA and all bearing their own advantages and limitations. Most laboratories use the indirect immunofluorescence (IIF) assay based on HEp-2 cell substrates. Due to the subjectivity of this diagnostic platform, automated digital reading systems have been developed during the last decade. In addition, solid phase immunoassays using well characterized antigens have gained widespread adoption in high throughput laboratories due to their ease of use and open automation. Despite all the advances in the field of ANA detection and its contribution to the diagnosis of SARD, significant challenges persist. This review provides a comprehensive overview of the current status on ANA testing including automated IIF reading systems and solid phase assays and suggests an approach to interpretation of results and discusses meeting the problems of assay standardization and other persistent challenges.

Personalised medicine in autoimmune diseases: myth or reality?

Progress in understanding the power of genomics, proteomics, metabolomics and other ‘omics' has sharpened perspectives of clinical medicine, particularly in appreciating that in the realm of therapeutics, ‘one size does not fit all'. This is leading to the rapid emergence of personalised medicine (PM) and related approaches such as pharmacogenomics. PM is not an entirely new concept because it has been practiced in many disciplines, most notably oncology, for well over a decade. However, with the availability of newer multiplexed and related high throughput array technologies, health care providers and payers, along with the therapeutic and diagnostic industries are increasingly focused on the potential advantages of PM. The use of PM in rheumatoid arthritis and related systemic autoimmune rheumatic diseases is emerging as an important consideration. This session will highlight the background information leading to the rapid emergence of PM, the compelling cases for PM, the technologies at our disposal, the essential growing role of diagnostic immunology in a successful PM enterprise and the caveats the may hinder wide adoption of PM in the foreseeable future.

THU0319 Determination of the Serological Profiles in Anti-Ro-52-Positive Patients with Systemic Autoimmune Rheumatic Diseases.

BackgroundRo-52 is an interferon (IFN)-inducible protein of the tripartite motif (TRIM) family.Antibodies against Ro-52 have been described in patients with different autoimmune diseases such as systemic lupus erythematosus (SLE) and...

THU0346 Dnase Activity of Polyclonal IgGs – A Putative Serological Marker in Patients with Spondyloarthritides

BackgroundAntibodies executing catalytic activity are referred to as antibody enzymes or short “abzymes” and may have diagnostic relevance. Despite several reports on the occurrence of DNase abzymes in systemic autoimmune...

AB0735 Antinuclear antibodies in aged people without signs of autoimmune disease

BackgroundAnti-nuclear antibodies (ANA) are a hallmark in the diagnosis of systemic autoimmune rheumatic diseases (SARD). Their occurrence in several diseases like systemic lupus erythematodes (SLE), systemic scleroderma, Sjögren’s syndrome, myositis...

Clinical performance evaluation of a novel rapid response chemiluminescent immunoassay for the detection of autoantibodies to extractable nuclear antigens

BackgroundWe analyzed the performance of a novel ENA screening chemiluminescent immunoassay (CIA) and the confirmation QUANTA Flash tests. MethodsSera (n=1079) from patients referred to a rheumatology clinic were screened by QUANTA Flash ENA7 (INOVA Diagnostics). All positive (n=89) and a matched control group (n=90) were reflexed for autoantibodies to the individual antigens. Moreover, sera from patients with systemic lupus erythematosus (SLE, n=252), systemic sclerosis (SSc, n=64), polymyositis/dermatomyositis (PM/DM, n=72), Sjögren's syndrome (SjS, n=39) as well as disease controls (n=605) were tested by ENA7 CIA and by Quanta Lite ENA6 ELISA (INOVA). Results89/1079 (8.3%) samples were ENA7 CIA positive with the following reactivity profile: RNP (36.0%), Sm (13.5%), Scl-70 (9.0%), Jo-1 (0.0%), Ro60 (44.9%), Ro52 (39.3%) and SS-B (24.7%). In the negative group, the reactivity profile was: RNP (1.1%), Sm (1.1%), Scl-70 (2.2%) and 0.0% for Jo-1, Ro60, Ro52 and SS-B. The positive/negative/total agreements (ENA7 CIA vs. confirmation assays) were 95.3%/91.5%/93.3%. The sensitivity of the ENA7 CIA was 62.3% in SLE, 54.7% in SSc, 92.3% in SjS, 50.0% in PM/DM, and 61.8% in the total systemic autoimmune rheumatic disease (SARD) population (specificity 95.0%). ConclusionThe QUANTA Flash ENA7 CIA is a reliable screening test.

Deoxyribonuclease activity of polyclonal IgGs: a putative serological marker in patients with spondyloarthritides

Antibodies executing catalytic activity are referred to as antibody enzymes or short "abzymes" and may have diagnostic relevance. Abzymes with deoxyribonuclease (DNase) activity have been demonstrated in patients with autoimmune and infectious diseases. Despite several reports on the occurrence of DNase abzymes in systemic autoimmune rheumatic diseases, conclusive data about DNase activity of antibodies in patients with spondyloarthritides (SpAs) are lacking. In recent cross-sectional studies evaluating levels of IgG DNase activity in patients with psoriatic arthritis (PsA), reactive arthritis (ReA), and ankylosing spondylitis (AS), DNase activity of IgG has been assessed by the rivanol clot method and confirmed by agarose gel electrophoresis. Remarkably, levels of IgG DNase activity were significantly higher in sera of SpA patients than those in control subjects. In patients with PsA, ReA, and AS, a positive correlation of DNase IgG activity with synovitis, disease activity, and stage of spondylitis was observed, respectively. Given the involvement of autoimmune reactions in cytolysis and connective tissue degradation in PsA, ReA, and to a lesser extent in AS, abzymes might have an impact on the pathophysiology of SpAs. Detection of IgG DNase activity in patients suffering from SpA represents an exciting new research field and may assist in the differential diagnosis of SpA.