Diagnosis Of Systemic Autoimmune Rheumatic Diseases Research Articles

Central Nervous System Involvement in Systemic Autoimmune Rheumatic Diseases-Diagnosis and Treatment.

Central nervous system (CNS) involvement in autoimmune rheumatic diseases represents a significant challenge for clinicians across all specialties. While most reviews on the subject focus on neurological manifestations within a specific rheumatic disease, few descriptions shift from neurological clinical syndromes to achieve rheumatological diagnoses. This narrative review aims to synthesize current knowledge on the diagnosis and management of CNS manifestations occurring in the most prevalent rheumatic conditions in adults. We searched the MEDLINE database using the terms "central nervous system", "rheumatic diseases", "systemic lupus erythematosus", "rheumatoid arthritis", "Sjögren syndrome", and "vasculitis". The search strategy included review articles from 2019 to 2024, published in English, Spanish, or Portuguese. We explored the pathophysiological mechanisms linking autoimmunity to CNS pathology, emphasizing the role of syndromic reasoning, autoantibody profiles, and imaging modalities as tools for diagnosis and determination of inflammatory activity. The review also discusses differential diagnoses through a stepwise approach to neurological syndromes, summarized in diagnostic flowcharts, and presents updated treatment options. Although our approach is primarily semiology-based, the complexity of the subject invites future endeavors involving new technologies, such as functional MRI, MR spectroscopy, and nuclear medicine.

Detection of systemic autoimmune diseases in an ongoing assessment program for hand arthralgias. A comparative analysis with inflammatory and non-inflammatory arthropathies.

Arthralgias are prevalent in systemic autoimmune rheumatic diseases (SARD), emphasizing the need for early recognition. This study aimed to estimate SARD frequency and compare clinical, laboratory, and imaging findings among SARD, non-inflammatory arthralgia (NIA), and RA in patients with hand arthralgias. A prospective evaluation program included individuals aged ≥18 with hand arthralgias. Baseline assessments covered clinical, laboratory, ultrasound, and radiography. Follow-up diagnoses categorized patients into SARD, NIA, and RA groups. Comparison between groups was performed using parametric and non-parametric tests. Two multivariate logistic regression analyzes were performed using the final diagnosis of SARD as the dependent variable (NIA and RA). ROC curves were calculated in those variables that presented an independent association in the multivariate analysis. Among 1053 patients, 9.6% were SARD (SLE 47%). Comparing SARD with NIA revealed higher CRP levels, power Doppler, less rhizarthrosis in ultrasound, and more ANA positivity in SARD patients. Distinct differences were observed between SARD and RA patients in terms of pain levels, swollen joints, metacarpophalangeal involvement and morning symptoms. Diagnostic markers demonstrated specific sensitivities and specificities: ANA for SARD versus NIA (82%, 34%), US not finding rhizarthrosis for SARD versus NIA (66%, 85%), CRP (cut-off >2.5 mg/L) sensitivity 52%, specificity 60%, AUC 0.62, RA antibodies (RF, 11 IU/mL) sensitivity 76%, specificity 74%, AUC 0.8, ACPA (1.25) sensitivity 50%, specificity 98%, AUC 0.7, ANA+ sensitivity 95%, specificity 32%, AUC 0.7, and US absence of synovitis sensitivity 82%, specificity 34%, AUC 0.75. This study highlights distinct clinical, laboratory, and imaging features differentiating SARD-related hand arthralgia from non-SARD hand arthralgia and RA.

Peripheral Neuropathy in Systemic Autoimmune Rheumatic Diseases-Diagnosis and Treatment.

Peripheral neuropathy (PN) is frequently observed in systemic rheumatic diseases and is a challenge in clinical practice. We aimed to review the evidence on the subject and proposed a comprehensive approach to these patients, facilitating diagnosis and management. We searched the MEDLINE database for the terms (and its respective Medical Subject Headings (MeSH) terms): "peripheral neuropathy" AND "rheumatic diseases" OR "systemic lupus erythematosus", "rheumatoid arthritis", "Sjogren syndrome", and "vasculitis" from 2000 to 2023. This literature review focuses on the diagnostic workup of PNs related to systemic lupus erythematosus, Sjögren's syndrome, rheumatoid arthritis, and systemic vasculitis. For every type of PN, we provide a pragmatic flowchart for diagnosis and also describe evidence-based strategies of treatment.

Interferon and interferon-induced cytokines as markers of impending clinical progression in ANA+ individuals without a systemic autoimmune rheumatic disease diagnosis

BackgroundElevated levels of interferons (IFNs) are a characteristic feature of systemic autoimmune rheumatic diseases (SARDs) and may be useful in predicting impending symptomatic progression in anti-nuclear antibody-positive (ANA+) individuals lacking a SARD diagnosis. Typically, these are measured by their effect on gene expression in the blood, which has limited their utility in clinical settings. Here, we assessed whether the measurement of serum IFN-α or selected IFN-induced cytokines accurately mirrors IFN-induced gene expression in ANA+ individuals and investigated their utility as biomarkers of clinical progression.MethodsA total of 280 subjects were studied, including 50 ANA− healthy controls, 160 ANA+ individuals without a SARD diagnosis (96 asymptomatic, 64 with undifferentiated connective tissue disease), and 70 SARD patients. IFN-induced gene expression was measured by nanoString and cytokine levels by ELISA or Simoa. ANA+ individuals lacking a SARD diagnosis who had the new onset of SARD criteria over the subsequent 2 years were defined as progressors.ResultsMeasurement of IFN-α levels by high-sensitivity ELISA or Simoa correlated much better with IFN-induced gene expression than measurement of CXCL-10 or Galectin-9 levels. Despite this, high CXCL-10 and Galectin-9 levels were better predictors of subsequent progression in ANA+ individuals than measures of IFN-α or IFN-induced gene expression with the optimal combination of predictive cytokines (CXCL-10 and IFN-α as measured by ELISA), resulting in a specificity and positive predictive value of 100%.ConclusionEasily performed ELISA assays for CXCL-10 and IFN-α can be used to predict ANA+ individuals at high risk of imminent symptomatic progression.

Prevalence and clinical characteristics of the dense fine speckled pattern: Indirect immunofluorescence‐antinuclear antibody screening in the Chinese population

AbstractTo investigate the prevalence and clinical significance of the dense fine speckled (DFS) pattern in a large‐scale cohort of Chinese patients. Data on the antinuclear antibody (ANA) and extractable nuclear antigen (ENA) autoantibody obtained from 165 498 patients who attended Peking Union Medical College Hospital from January 2019 to December 2021 were retrospectively analysed. The prevalence of the DFS pattern was 1.14%, and it mainly appeared in young patients (≤24 years old). A higher positive rate of the DFS pattern was observed in patients with dermatosis (18.12%) and systemic autoimmune rheumatic diseases (SARDs) (13.53%). The DFS pattern titre was mostly low or medium (≤1:160). A higher titre was associated with an increased risk of SARDs (p < .001), dermatosis (p = .015) and pulmonary disease (p = .016). In 37 patients with ENA autoantibody positivity, anti‐SSA antibody was the most common (2.55%). If the low titre (<1:160) or the DFS pattern with negative ENA autoantibody were to be used as exclusion criteria for SARDs, the diagnosis would have been missed in 42 or 77 patients, respectively. The prevalence of the DFS pattern was low in ANA test samples and was more common in patients with dermatosis and SARDs, but the titre was usually higher in patients with SARDs. There was no evidence that the DFS pattern could be used as an exclusion criterion for SARDs diagnosis. The DFS pattern was associated with certain pathological states, which may inform the clinical significance of the DFS pattern.

Cardiovascular Medication Use And Timing Of Incident Heart Failure In Patients With Systemic Autoimmune Rheumatic Diseases: A Single-Center Experience

<h3>Background</h3> : Systemic autoimmune rheumatic diseases (SARDs), including systemic sclerosis (SSc), systemic lupus erythematosus (SLE), and rheumatoid arthritis (RA), are associated with an increased independent risk of heart failure (HF). <h3>Hypothesis</h3> : We hypothesize that cardiovascular (CV) drugs prescribed at time of SARD diagnosis may be associated with delayed onset of incident HF. <h3>Methods</h3> : We reviewed electronic health records from a large multispecialty institution of adult patients with SARDs from 2000-2020. Demographic data, SARD diagnosis, HF and comorbidity status, and cardiovascular medication use data were extracted retrospectively. CV drugs included were angiotensin converting enzyme inhibitors (ACE-i), angiotensin receptor blockers (ARBs), beta blockers (BBs), calcium channel blockers (CCBs), and thiazide diuretics. Baseline was defined as time of SARD diagnosis. Inclusion criteria were SSc, SLE, or RA diagnosis. Patients with HF at baseline were excluded. Cox proportional hazards regression was performed to investigate the association between CV drugs exposure at baseline and time to incident HF, adjusting for traditional risk factors (age, sex, hypertension, diabetes, coronary artery disease, myocardial infarction, and chronic kidney disease). <h3>Results</h3> : In our study cohort, we identified 3,714 patients with SSc (5.7%), 15,940 patients with SLE (24.7%), and 44,966 patients with RA (69.6%), among which 14.4% of SSc, 12.2% of SLE, and 10.5% of RA patients developed incident HF during follow-up. In our study cohort (n = 64,620), ARB (aHR: 1.1 [1.0-1.2]; p = 0.005) and thiazide (aHR: 1.2 [1.1-1.2]; p <0.001) use were significantly associated with decreased time to incident HF, while BB (aHR: 0.68 [0.61-0.75]; p <0.001) use was associated with increased time to HF. In SSc patients (compared with no CV drugs), ACE-i (aHR: 1.5; 95% CI [1.14-1.9]; p = 0.004), ARB (aHR: 1.4 [1.06-1.9]; p = 0.018), and thiazide (aHR: 1.5 [1.15-1.9]; p=0.003) use were significantly associated with decreased time to incident HF. Baseline BB use had near significant association with increased time to incident HF in SSc (aHR: 0.73 [0.51-1.0]; p = 0.079). In SLE patients (compared with no CV drugs), baseline thiazide use was associated with decreased time to incident HF (aHR: 1.2 [1.0-1.4]; p = 0.01), and BB use was associated with increased time to incident HF (aHR: 0.71 [0.57-0.89]; p = 0.003). In RA patients, baseline ARB (aHR: 1.1 [1.0-1.2]; p = 0.026) and thiazide (aHR: 1.1 [1.0-1.2]; p = 0.003) were associated with decreased time to incident HF and BB use was associated with increased time to incident HF (aHR: 0.68 [0.61-0.76]; p <0.001). <h3>Conclusion</h3> In our single-center experience, the use of beta-blockers at the time of SARD diagnosis was associated with delayed onset of HF. Further investigations into the potential cardioprotective effects of beta-blockers in patients with SARDs are warranted.

Dense fine speckled immunofluorescence pattern in a Chinese population: Prevalence and clinical association.

ObjectiveTo provide information on the prevalence and possible clinical association in a Chinese population for medical practice of the dense fine speckled pattern (DFS pattern).MethodsA retrospective study was conducted with patients who had the DFS pattern from June 2018 to December 2019 in West China Hospital.ResultsA total of 469 patients (1.27% of patients with positive anti‐nuclear antibody indirect immunofluorescence (ANA IIF) test results) revealed the DFS pattern, of which 92.96% had isolated DFS pattern and 23.67% had titers above/equal to 1:320. The average age of patients with the DFS pattern was 43.45 years, and females accounted for 76.97% of them. Ten different kinds of diseases made up the vast majority of the disease spectrum, in which inflammatory or infectious diseases (46.11%), mental diseases (21.45%), and systemic autoimmune rheumatic diseases (SARDs) (18.23%) ranked in the top three. The most common SARDs were rheumatoid arthritis (RA), undifferentiated connective tissue disease (UCTD), and systemic lupus erythematosus (SLE). Forty‐six patients (10.55%) had positive or suspicious extractable nuclear antigen (ENA) antibodies test results and a higher risk of suffering from SARDs. Forty‐seven patients would be missed if the DFS pattern with negative ENA antibodies test result was considered as exclusion criterion of SARDs.ConclusionsThe DFS pattern is basically isolated and with low titer. It is unwise to exclude the diagnosis of SARDs only depending on the appearance of the DFS pattern. Autoimmune diseases‐related antibodies, clinical information of patients, and long‐term follow‐up are of great importance to avoid missed or delayed diagnosis of SARDs.

Diagnostic value of monospecifc DFS70 antibodies in systemic utoimmune rheumatic diseases

The detection in serum of monospecifc antibodies that induce a dense fne-speckled fluorescence when interacting with the DFS70 / LEDGF / p75 nuclear antigen is negatively associated with the development of systemic autoimmune rheumatic diseases (SARD) and increases the diagnostic specifcity of the screening study of antinuclear antibodies (ANA) using indirect immunofluorescence on HEp-2 cells (IIF-HEp-2). The results of assessing the clinical signifcance of anti-DFS70 antibodies vary depending on the test systems and the selection of patient groups. The aim of this work is to study the frequency of detection of monospecifc anti-DFS70 antibodies in blood serum in healthy individuals and patients with SARD. Sera of 74 healthy donors and 59 patients with SARD were studied (27 – systemic lupus erythematosus – SLE, 15 – Sjogren's syndrome – SjS, 17 – rheumatoid arthritis – RA). Classical antinuclear antibodies (ANA) and anti-DFS70 antibodies were determined by IIF using a mixture of standard and genetically engineered DFS70-KO HEp-2 cells that do not express DFS70 / LEDGF / p75 as a substrate. 14.9% of healthy donors and 83.1% of SARD patients (96.3% – SLE, 100.0% – SS, 47.1% – RA) were seropositive for antinuclear factor (ANF). Classical ANA with homogeneous, speckled, nucleolar, cytoplasmic, mixed types of fluorescence and the absence of anti-DFS70 antibodies were found in all ANF-positive patients with SARD and in 8.1% of healthy donors. Monospecifc anti-DFS70 antibodies without classical ANA were detected in 6.8% of healthy individuals and were absent in SARS. Among ANF-positive healthy donors, the frequency of isolated detection of anti-DFS70 antibodies was 45.5%. The detection of monospecifc anti-DFS70 antibodies can be considered as a potential predictive marker for excluding the diagnosis of SARD in ANF-positive patients with no or unclear clinical signs of these diseases.

Comparison study of bead-based and line-blot multiplex ANA immunoassays in the diagnosis of systemic autoimmune rheumatic diseases

Detection of antinuclear antibodies (ANA) by immunofluorescence assay (IFA) is increasingly substituted by multiplex bead-based immunoassay (MBA) and line-blot immunoassay (LIA). This study is to compare the diagnostic performance of MBA and LIA ANA assays on clinically characterized patient samples. A total of 728 serum samples from 385 patients with systemic autoimmune rheumatic diseases (SARD), 204 patients with non-SARD diseases, and 139 apparently healthy subjects were tested with the BioPlex 2200 ANA Screen and EuroLine ANA Profile 3 as the representative MBA and LIA technologies and HEp-2 ANA IFA. Clinical data were collected independent of laboratory analysis and later related to the ANA test results. The clinical diagnostic performances were analyzed using Analyse-it software. The MBA demonstrated higher area under curve (AUC) compared to LIA (0.814 vs 0.761, p = 0.002) and HEp-2 IFA (0.814 vs 0.771, p = 0.008). The MBA and LIA ANA methods showed higher specificity (83.8% and 77.0% vs 67.6%, p < 0.001 and p = 0.005) but lower sensitivity (79.0% and 75.3% vs 86.5%, p < 0.001) compared to HEp-2 IFA. The MBA and LIA ANA revealed substantial to excellent agreements on specific antinuclear antibodies except anti-dsDNA, with the total agreement from 92.3 to 99.9% and Cohen's kappa from 0.71 to 0.98. The MBA demonstrated significantly higher sensitivity (58.1% vs 19.8%, p < 0.001) and comparable specificity (95.9% vs 97.5%, p = 0.221) on anti-dsDNA assay for the diagnosis of SLE compared to LIA. The MBA and LIA ANA assays have higher specificity but lower sensitivity compared to HEp-2 IFA. There are good agreements between MBA and LIA ANA for the specific antinuclear antibodies except for anti-dsDNA. The MBA ANA demonstrated better assay performance compared to LIA as the MBA possesses higher sensitivity and specificity in the diagnosis of SARD. Key Points • The multiplex bead-based immunoassay (MBA) ANA outperformed line-blot immunoassay (LIA) and traditional HEp-2 IFA. • There are good agreements between the MBA BioPlex 2200 ANA Screen and LIA EuroLine ANA Profile 3 for the most of specific antinuclear antibodies except anti-dsDNA. • Additional anti-dsDNA testing is suggested when EuroLine ANA Profile 3 is used for the aid of SLE diagnosis and management. • The positive predictive value of both multiplex ANA assays can be substantially increased without significantlyaffecting negative predictive value by using at least two specific antinuclear antibodies for reporting a positive ANAresult.

Investigation of the Clinical Significance of Anti-Dense Fine Speckled 70 (anti-DFS70) Autoantibody and Determination of Accompanying Pathologies

Autoantibodies targeting nuclear and cytoplasmic autoantigens are used as markers in the diagnosis and classification of systemic autoimmune rheumatic diseases (SARD). The dense fine speckled (DFS) pattern is characterized by the fine-granular fluorescence of the nuclei in the interphase and the metaphase chromatin. DFS70 antibodies have been reported in healthy individuals, various autoimmune disorders, infection, cancer and inflammatory conditions. But there is still lack of information about its clinical significance. This study aimed to investigate the clinical significance of anti-DFS70 autoantibodies and the determination of accompanying pathologies. A total of 5710 serum samples routinely requested for ANA screening were tested between 2017 and 2019. Antinuclear antibody (ANA) and dsDNA were performed by indirect immunofluorescence method (IIF) (Euroimmun, Germany). Immunoblot (IB) method was used for the extractable nuclear antigen profile (ENA) (Euroimmun, Germany). Demographic and clinical data, were investigated from the medical records. Among 5710 samples tested for ANA, 23.7% were ANA positive by IIF. Mean age of the patients were 47.9 and 79.5% were female. Only 8.1% of the study group had SARD. The frequency of DFS pattern by ANA-IIF was 6.0% (342/5710), (mean age ± SD= 44.4 ± 16.7, 88% female). DFS70 pattern-positive patients were sub-grouped according to their diagnosis. SARD were detected 10.8% (mean age ± SD= 55.12 ± 14.10) in DFS70 pattern positive patient group (RA 6.1%, SS 2.6%, SLE 0.9%, SSc 0.6%, UCTD 0.6%). Autoantibodies accompanying anti-DFS70 antibody were determined as Ro-52, SS-A, nucleosome, histone, AMA-M2, dsDNA, respectively. Non-SARD diseases were determined in 89.2% of the patients with positive DFS70 pattern. Non-SARD diseases were detected as musculoskeletal complaints (47.4%), other rheumatic diseases like fibromyalgia (14.3%), dermatological diseases (9.4%), gastrointestinal system diseases (5.6%), hematological disorders (3.8%), thyroid /parathyroid diseases (3.5%), allergic diseases (2.3%), neurological diseases (2.3%) and neoplasia (breast cancer) (0.6%). The anti-DFS70 autoantibody is widely used to exclude the diagnosis of SARD in the absence of concomitant SARD-related autoantibodies. It has been observed that anti-DFS70 autoantibody may be associated with non-SARD rheumatic diseases and in many diseases (dermatological, gastrointestinal system, hematological, thyroid diseases) related to other systems. Therefore it is essential to evaluate these pathologies in patients positive for anti-DFS70 antibodies.

Serological abnormalities that predict progression to systemic autoimmune rheumatic diseases in antinuclear antibody-positive individuals.

We investigated the autoantibody (autoAb) profiles in ANA+ individuals lacking systemic autoimmune rheumatic disease (SARD) and early SARD patients to determine the key differences between these groups and identify factors that are associated with an increased risk of symptomatic progression within the next 2 years in ANA+ individuals. Using custom antigen (Ag) microarrays, 144 IgM and IgG autoAbs were surveyed in 84 asymptomatic and 123 symptomatic (48 UCTD and 75 SARD patients) ANA+ individuals. AutoAbs were compared in ANA+ individuals lacking a SARD diagnosis with ≥2 years follow-up (n = 52), including all those who demonstrated progression (n = 14) during this period, with changes over time assessed in a representative subset. We show that ANA+ individuals have autoAb to many self-Ags that are not being captured by current screening techniques and very high levels of these autoAbs are predominantly restricted to early SARD patients, with SLE patients displaying reactivity to many more autoAgs than the other groups. In general, the symptoms that developed in progressors mirrored those seen in SARD patients with similar patterns of autoAbs. Only anti-Ro52 Abs were found to predict progression (positive predictive value 46%, negative predictive value 89%). Surprisingly, over 2 years of follow-up the levels of autoAbs remained remarkably stable regardless of whether individuals progressed or not. Our findings strongly argue that development of assays with an expanded set of auto-Ags and enhanced dynamic range would improve the diagnostic and prognostic ability of autoAb testing.

A cohort study: The Association Between Autoimmune Disorders and Leptospirosis

There are limited studies on the association between systemic autoimmune rheumatic diseases (SARDs) and leptospirosis. Therefore, this study aims to identify the effects of leptospirosis on the risks of developing SARDs with a nationwide retrospective cohort study. Patients with leptospirosis who did not have a diagnosis of SARDs before the index date were enrolled from the Taiwan National Health Insurance Research Database between 2000 and 2010, as the leptospirosis cohort. For each patient with leptospirosis, one control without a history of leptospirosis and SARDs was randomly selected (non-leptospirosis cohort). Cox proportional hazards regression models were used to analyze the risk of SARDs according to sex, age, and comorbidities. Among the 23 million people in the cohort, 3,393 patients with leptospirosis (68.91% men, mean age 52.65 years) and 33,930 controls were followed for 18,778 and 232,999 person-years, respectively. The incidence of SARDs was higher in the leptospirosis cohort than in the non-leptospirosis cohort (1.38 vs 0.33 per 1000 person-years), with a hazard ratio (HR) of 4.42 (95% confidence interval [CI] = 2.82–6.92). The risk of developing SARDs was highest for leptospirosis patients aged ≥65 years (HR = 2.81% CI = 1.07–7.36) compared with patients aged ≤39 years. Patients with leptospirosis have a 4.42-fold higher risk of SARDs than that in the general population. Further research is warranted to investigate the mechanism underlying this association.

Fatigue severity in anti-nuclear antibody-positive individuals does not correlate with pro-inflammatory cytokine levels or predict imminent progression to symptomatic disease

BackgroundFatigue is a common symptom of systemic autoimmune rheumatic disease (SARD). Patients with SARD have a protracted pre-clinical phase during which progressive immunologic derangements occur culminating in disease. In this study, we sought to determine when fatigue develops and whether its presence correlates with inflammatory factors or predicts disease progression.MethodsAnti-nuclear antibody (ANA)-negative healthy controls (HCs) and ANA-positive participants with no criteria, at least one clinical criteria (undifferentiated connective tissue disease, UCTD), or meeting SARD classification criteria were recruited. Fatigue was assessed using a modified version of the FACIT-F questionnaire and the presence of fibromyalgia determined using a questionnaire based on the modified 2010 ACR criteria. Peripheral blood expression of five IFN-induced genes was quantified by NanoString and the levels of IL-1β, IL-6, or TNF-α by ELISA.ResultsFatigue was as prevalent and severe in individuals lacking SARD criteria as it was in UCTD and SARD. Overall, ~ 1/3 of ANA+ subjects met fibromyalgia criteria, with no differences between sub-groups. Although fatigue was more severe in these individuals, those lacking fibromyalgia remained significantly more fatigued than ANA− HC. However, even in these subjects, fatigue correlated with the widespread pain index and symptom severity scores on the fibromyalgia questionnaire. Fatigue was not associated with elevated cytokine levels in any of the ANA+ sub-groups and did not predict imminent disease progression.ConclusionsFatigue is common in ANA+ individuals lacking sufficient criteria for a SARD diagnosis, correlates with fibromyalgia-related symptoms, and is not associated with inflammation or predictive of disease progression.

Distinctive features of positive anti-cell antibody tests (indirect immunofluorescence on HEp-2 cells) in patients with non-autoimmune diseases.

The objective of this study was to determine whether characteristics of positive results in the indirect immunofluorescence assay on HEp-2 cells for anti-cell antibodies (HEp-2 IFA) differ between patients with non-autoimmune diseases (NADs) and patients with systemic autoimmune rheumatic diseases (SARDs). Cross-sectional observational study comparing HEp-2 IFA test results in three groups: (a) 558 NAD patients comprising four subgroups (cancer ( n = 95), infectious diseases ( n = 148), psychiatric diseases ( n = 163), common non-infectious chronic diseases ( n = 152)); (b) 194 SARD patients; (c) 1217 healthy individuals (HIs). Sera were tested at 1:80 dilution and diluted to the end titer. Slides were analyzed by two independent blinded examiners. A positive HEp-2 IFA test occurred in 102 (18.3%) NAD patients, 170 (87.6%) SARD patients and 150 (12.3%) HIs. The four NAD subgroups did not differ regarding HEp-2 IFA frequency, titer or pattern. HEp-2 IFA titer was higher in NAD patients than in HIs and both had lower titer than SARD patients. Nuclear dense fine speckled pattern was more frequent in NAD patients and HIs than in SARD patients ( p < 0.001). Nuclear homogeneous and nuclear coarse speckled patterns were more frequent in SARD patients than in the other groups ( p < 0.001). The nuclear fine speckled pattern was prevalent in all three groups, but presented a gradient in titer across them; HIs and NAD patients had low and intermediary titers, which were significantly lower than in SARD patients ( p < 0.001). Positive HEp-2 IFA frequency, pattern and titer present differential features in NAD and SARD patients, and this attribute adds value to the test in the diagnosis of SARDs.

590: Pregnancy outcomes pre and post systemic autoimmune rheumatic diseases: a population-based cohort study

To assess fetal and maternal outcomes pre and post a diagnosis of a systemic autoimmune rheumatic disease (SARD). We conducted a retrospective cohort study from a perinatal registry including all pregnancies in British Columbia from January 1st, 2002 to December 31st, 2012. SARDs was defined as one ICD-9/10 hospital code, or =/> 2 ICD-9/ICD-10 MSP codes at least 2 months apart in a 2 -year window. All connective tissue diseases were included: systemic lupus erythematosus, scleroderma/systemic sclerosis, Sjogren’s syndrome, dermatomyositis, polymyositis. SARDs exposure was based on diagnosis before or after date of conception. The groups were defined as post-SARDs (pregnancy following SARDs diagnosis) and pre-SARDs (pregnancy preceding SARDs diagnosis). Logistic, Cox and Poisson regression models evaluated the effects of SARDs on perinatal outcomes (small for gestational age [SGA], congenital anomalies [CA], preterm delivery, major infection in baby) and maternal outcomes (major infections). All models were adjusted for maternal prescription medications, comorbidities, prior pregnancy outcomes, and BMI. Of 405,538 total pregnancies, 1400 had SARDs. 1011 pregnancies were post-SARDs, and 389 were pre- SARDs. Odds ratios (OR) for the association of SARD’s with infants born SGA were increased for post- and pre-SARDs groups compared to non-SARDs pregnancies. The ORs for the association of SARDs with CA were increased only in the post-SARD’s group. Hazard ratios (HR) for the effect of post- and pre-SARDs on preterm delivery were increased. Count ratios (CR) for the association of SARDs with a serious newborn infection were increased only in the pre-SARDs group. No increased risk seen for serious maternal infections. Increased risk of SGA, CA and preterm delivery was found in patients with SARD’s. The risk of SGA, preterm delivery and newborn infections was increased prior to a SARD diagnosis. No association was seen between SARDs and maternal infections.

Association between PM2.5 and Systemic Autoimmune Rheumatic Diseases: A Cohort Study in Taiwan from 2001 to 2011

Background: Systemic autoimmune rheumatic diseases (SARDs) are a group of diseases with abnormally inflammatory reactions, such as dermatomyositis (DM), polymyositis (PM), systemic sclerosis (SSc). The pathogenesis of systemic autoimmune diseases is still unclear. Only a few studies accessed the relation between exposure to air pollution and systemic inflammation and provide inconsistent results. We conducted a prospective cohort study to investigate the associations between fine particulate matter (PM2.5) and SARDs, namely DM, PM, SSc, in Taiwan.Methods: The study population were obtained from Taiwan National Health Insurance Research Database (NHIRD) and followed up from 2001 to 2011. All participants were followed end when diagnosis of SARDs (DM, PM, SSc), or death, or end of the study. We developed a model integrated 3-km AOD with meteorological parameters and land use data to predict daily PM2.5 concentrations across Taiwan. We performed a time dependent Cox models to assess the effects of yearly average PM2.5 on SARDs (DM, PM, SSc). The results were reported as hazard ratios (HRs) with 95% confidence interval (CI).Results: A total of 3119 DM cases, 3259 PM cases, and 2824 SSc cases were identified during the study period. The mean age of DM, PM, and SSc cases were 54.4&amp;#177;18.7, 53.8&amp;#177;16.8, and 49.9&amp;#177;15.9 years, respectively. After adjusting for sex, age, and socioeconomic status, the results showed that exposure to an Interquartile range (IQR) increase in PM2.5 level (14.29 &amp;#956;g/m3) were associated with an approximately 48% increased risk of DM (95% CI 1.39&amp;#172;-1.59) and a 23% increased risk of PM (95% CI 1.16-1.32). We did not observe significant associations between PM2.5 and SSc.Conclusions: Our study suggests that exposure to PM2.5 may increase the risk of DM and PM. The future studies would be needed to confirm these associations, and explore potential toxicants on SARDs other than PM2.5.

Filling the gaps in SARDs research: collection and linkage of administrative health data and self-reported survey data for a general population-based cohort of individuals with and without diagnoses of systemic autoimmune rheumatic disease (SARDs) from British Columbia, Canada

PurposeSystemic autoimmune rheumatic diseases (SARDs) are a group of debilitating autoimmune diseases, including systemic lupus erythematosus and related disorders. Assessing the healthcare and economic burden of SARDs has been challenging:...

Presence of an interferon signature in individuals who are anti-nuclear antibody positive lacking a systemic autoimmune rheumatic disease diagnosis

BackgroundElevated levels of type I interferons (IFNs) are a characteristic feature of the systemic autoimmune rheumatic diseases (SARDs) and are thought to play an important pathogenic role. However, it is unknown whether these elevations are seen in anti-nuclear antibody–positive (ANA+) individuals who lack sufficient criteria for a SARD diagnosis. We examined IFN-induced gene expression in asymptomatic ANA+ individuals and patients with undifferentiated connective tissue disease (UCTD) to address this question.MethodsHealthy ANA− control subjects and ANA+ titre (≥1:160 by immunofluorescence) participants meeting no criteria, meeting at least one criterion (UCTD) or meeting SARD classification criteria were recruited. Whole peripheral blood IFN-induced and BAFF gene expression were quantified using NanoString technology. The normalized levels of five IFN-induced genes were summed to produce an IFN5 score.ResultsThe mean IFN5 scores were increased in all ANA+ participant subsets as compared with healthy control subjects. We found that 36.8% of asymptomatic ANA+ and 50% of UCTD participants had IFN5 scores >2 SD above the mean for healthy control subjects. In all ANA+ subsets, the IFN5 score correlated with the presence of anti-Ro/La antibodies. In the asymptomatic ANA+ subset, this score also correlated with the ANA titre, whereas in the other ANA+ subsets, it correlated with the number of different ANA specificities. Development of new SARD criteria was seen in individuals with normal and high IFN5 scores.ConclusionsAn IFN signature is seen in a significant proportion of ANA+ individuals and appears to be associated with ANA titre and type of autoantibodies, rather than with the presence or development of clinical SARD symptoms.

The significance of autoantibodies to DFS70/LEDGFp75 in health and disease: integrating basic science with clinical understanding.

Antinuclear autoantibodies (ANAs) displaying the nuclear dense fine speckled immunofluorescence (DFS-IIF) pattern in HEp-2 substrates are commonly observed in clinical laboratory referrals. They target the dense fine speckled autoantigen of 70 kD (DFS70), most commonly known as lens epithelium-derived growth factor p75 (LEDGFp75). Interesting features of these ANAs include their low frequency in patients with systemic autoimmune rheumatic diseases (SARD), elevated prevalence in apparently healthy individuals, IgG isotype, strong trend to occur as the only ANA specificity in serum, and occurrence in moderate to high titers. These autoantibodies have also been detected at varied frequencies in patients with diverse non-SARD inflammatory and malignant conditions such as atopic diseases, asthma, eye diseases, and prostate cancer. These observations have recently stimulated vigorous research on their clinical and biological significance. Some studies have suggested that they are natural, protective antibodies that could serve as biomarkers to exclude a SARD diagnosis. Other studies suggest that they might be pathogenic in certain contexts. The emerging role of DFS70/LEDGFp75 as a stress protein relevant to human acquired immunodeficiency syndrome, cancer, and inflammation also points to the possibility that these autoantibodies could be sensors of cellular stress and inflammation associated with environmental factors. In this comprehensive review, we integrate our current knowledge of the biology of DFS70/LEDGFp75 with the clinical understanding of its autoantibodies in the contexts of health and disease.

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.