Altered serum metabolome as an indicator of paraneoplasia or concomitant cancer in patients with rheumatic disease.

OBJECTIVES: A timely diagnosis is imperative for curing cancer. However, in patients with rheumatic musculoskeletal diseases (RMDs) or paraneoplastic syndromes, misleading symptoms frequently delay cancer diagnosis. As metabolic remodelling characterises both cancer and RMD, we analysed if a metabolic signature can indicate paraneoplasia (PN) or reveal concomitant cancer in patients with RMD. METHODS: Metabolic alterations in the sera of rheumatoid arthritis (RA) patients with (n=56) or without (n=52) a history of invasive cancer were quantified by nuclear magnetic resonance analysis. Metabolites indicative of cancer were determined by multivariable regression analyses. Two independent RA and spondyloarthritis (SpA) cohorts with or without a history of invasive cancer were used for blinded validation. Samples from patients with active cancer or cancer treatment, pulmonary and lymphoid type cancers, paraneoplastic syndromes, non-invasive (NI) precancerous lesions and non-melanoma skin cancer and systemic lupus erythematosus and samples prior to the development of malignancy were used to test the model performance. RESULTS: Based on the concentrations of acetate, creatine, glycine, formate and the lipid ratio L1/L6, a diagnostic model yielded a high sensitivity and specificity for cancer diagnosis with AUC=0.995 in the model cohort, AUC=0.940 in the blinded RA validation cohort and AUC=0.928 in the mixed RA/SpA cohort. It was equally capable of identifying cancer in patients with PN. The model was insensitive to common demographic or clinical confounders or the presence of NI malignancy like non-melanoma skin cancer. CONCLUSIONS: This new set of metabolic markers reliably predicts the presence of cancer in arthritis or PN patients with high sensitivity and specificity and has the potential to facilitate a rapid and correct diagnosis of malignancy.

Dynamics of SARS-CoV-2 IgG antibodies and neutralising antibodies in rheumatic and musculoskeletal diseases patients with COVID-19.

OBJECTIVES: Rheumatic and musculoskeletal diseases (RMD) may exhibit different immune responses to novel coronavirus (COVID-19) infection compared to healthy individuals. While previous studies have primarily investigated changes in COVID-19-related antibodies post-vaccination for RMD patients, this study sought to explore the dynamics of SARS-CoV-2 IgG antibodies and neutralising antibodies (NAb) in RMD patients after COVID-19 infection. METHODS: In this longitudinal study, we monitored the SARS-CoV-2 IgG antibodies and NAb levels in RMD patients and healthy controls (HC) at 60 and 90 days post-COVID-19 infection. Chemiluminescent immunoassay was used to detect the levels of novel coronavirus-specific IgG (anti-S1/S2 IgG) antibodies and NAb. RESULTS: A total of 292 RMD patients and 104 HC were enrolled in the study. At both the 60-day and 90-day post-COVID-19 infection, RMD patients exhibited significantly lower levels of anti-S1/S2 IgG and NAb than those in the HC group (p<0.001). The anti-S1/S2 IgG antibody levels remained relatively stable, while the NAb levels in RMD patients could vary greatly between the 60th and 90th days. A logistic regression analysis revealed that the prior administration of glucocorticoids (GC), immunosuppressants, and b/tsDMARDs stood out as independent risk factors associated with reduced anti-S1/S2 IgG and NAb levels, irrespective of the specific RMD subtypes. CONCLUSIONS: GC and anti-rheumatic medications can potentially alter the production of specific antibodies, especially NAb, in RMD patients post-COVID-19 infection. These findings emphasise the importance of continuous monitoring for NAb fluctuations in RMD patients following a COVID-19 infection.

CA 15 - 3 in screening for systemic autoimmune rheumatic disease associated interstitial lung disease: a single center cross-sectional study.

INTRODUCTION: The natural course of interstitial lung disease (ILD) in patients with systemic autoimmune rheumatic diseases (SARD) varies significantly and is linked to considerable morbidity and mortality. Therefore, effective screening is crucial for early detection of SARD-ILD. Biomarkers associated with mucin 1, Krebs von den Lungen-6 (KL-6) and carbohydrate antigen 15-3 (CA 15-3), are increased in various ILD. This study aimed to assess the diagnostic accuracy of the serum biomarker CA 15-3 as a potential screening tool for ILD in patients newly diagnosed with SARD. METHODS: Conducted as a single-center cross-sectional study, the research included newly diagnosed SARD patients consecutively examined for ILD according to the algorithm. All included patients underwent chest high-resolution CT scans (HRCT), and serum levels of CA 15-3, KL-6, and lactate dehydrogenase (LDH) were measured and correlated with other variables associated with possible ILD presence. RESULTS: Serum biomarker levels, specifically CA 15-3 and LDH, are significantly higher in ILD-positive patients (P<0.001 for both). An inverse relationship is observed between higher FVC values and lower CA 15-3 levels (Rho=-0.291, P=0.007). Similarly, higher DLCO values are associated with lower CA 15-3 levels (Rho=-0.317, P=0.003). Our findings revealed that elevated CA 15-3 levels are positively correlated with higher levels of KL-6 (Rho=0.268, P=0.01) and LDH (Rho=0.227, P=0.04). With a cut-off value of 24 U/mL, CA 15-3 showed the highest sensitivity and specificity (AUC=0.807, specificity=95.7%, sensitivity=71.1%). CA 15-3 emerged as the most significant predictor of a positive HRCT finding, accurately classifying 83% of cases. CONCLUSION: These results suggest that CA 15-3 shows promise as a valuable serum biomarker for screening SARD patients for ILD in routine clinical practice.

[Importance of lysosomal storage diseases in rheumatology]. / Bedeutung lysosomaler Speicherkrankheiten in der Rheumatologie.

Lysosomal storage diseases are a group of rare hereditary metabolic diseases. Due to a deficiency of lysosomal enzymes, complex substrates accumulate in the lysosomes of various organs. Depending on the affected enzyme, this results in clinically variable and chronic progressive multiorgan diseases. Diagnosis is often delayed. As clinical symptoms include the musculoskeletal system, an awareness of lysosomal storage diseases is of relevance to (pediatric) rheumatologists. This article is focused on Mucopolysaccharidosis type I­S, Mucolipidosis type III, Gaucher disease and Fabry disease. When suspecting a lysosomal storage disease, enzyme activity should be determined in dried blood spots or leukocytes. For some diseases, specific biomarkers can additionally be analyzed. Diagnosis should be confirmed by genetic testing. As causal treatment options are available for three of the presented diseases, a timely diagnosis is very important.

The Diagnostic profile and clinical course of patients with rheumatic diseases in the medical intensive care unit.

Background/aim: Immunosuppressive and immunomodulatory treatments developed in recent years as a result of a better understanding of the pathophysiology of systemic rheumatic diseases (SRDs) improve the prognosis. Despite medical advances, individuals with SRDs at any stage may require intensive care and have a high mortality rate. The aim of this study was to investigate the demographic and clinical characteristics of patients with rheumatic diseases admitted to the intensive care unit (ICU), and the factors associated with the risk of mortality. Materials and methods: This was a retrospective, cross-sectional study that included patients with rheumatic diseases in the medical ICU. Factors of ICU 28-day mortality were identified by multiple-variable logistic analysis. Results: A total of 127 patients with SRDs admitted to the medical ICU were enrolled. Systemic lupus erythematosus (SLE) (32.3%) was the most common diagnosis of SRDs in patients admitted to the ICU. The reasons for admission to the ICU were combined infection and primary SRD flare-up (35.4%), primary SRD flare-up (22%), SRD-unrelated reasons (22%), infection (17.3%), drug side effects (3.9%), and SRD-related complications (0.8%). The most common organ dysfunctions before (49.6%) and during (77.2%) admission to ICU were in the respiratory system. The 28-day mortality was 78 (61.4%). While the maximum procalcitonin, serum lactate, and blood urea nitrogen (BUN) levels were higher in the nonsurvivor group, the platelet and serum albumin levels were statistically significantly lower than those in the survivor group (p < 0.05). Acute respiratory failure (ARF), the presence of septic shock, the need for invasive mechanical ventilation (IMV), BUN level, and low platelet-lymphocyte ratio (PLR) were significant in the final multiple-variable model. Conclusion: Significant predictors of mortality in patients with rheumatic diseases may include ARF, septic shock, the need for IMV, and high BUN and low PLR levels.

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

OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

High prevalence of steroid-induced glucose intolerance with normal fasting glycaemia during low-dose glucocorticoid therapy: an oral glucose tolerance test screening study.

OBJECTIVES: To evaluate the prevalence and risk factors of new-onset glucose metabolism impairment using an oral glucose tolerance test (OGTT) in patients with normal fasting glycaemia on long-term glucocorticoid (GC) treatment. METHODS: An OGTT was performed in 150 patients without a previous history of pre-diabetes or diabetes who were diagnosed with inflammatory rheumatic diseases and treated with GCs >3 months. All participants underwent clinical and biochemical evaluation for risk factors of diabetes: age, sex, current and cumulative dose of steroids, treatment duration, waist circumference, BMI, Homeostatic Model Assessment for Insulin Resistance, fasting insulin concentration, family history of diabetes, CRP, 28-joint DAS with CRP, type of connective tissue disease and trunk fat percentage measured by DXA. Logistic regression analysis was conducted to evaluate the association between the presence of impaired glucose tolerance (IGT) in the OGTT and analysed risk factors. RESULTS: A total of 102 patients (68%) had fully normal glucose tolerance. Diabetes, isolated impaired fasting glucose, isolated IGT and combined impaired fasting glucose + IGT was diagnosed in 3.3, 4.67, 19.33 and 4.67% of patients, respectively; 20% of participants had IGT or diabetes despite normal fasting glucose concentration. The median cumulative dose and current dose (5 mg) of GCs and treatment duration were similar compared with the normal glucose tolerance group. In a multivariate logistic regression model, only older age (particularly ≥50 years of age) and trunk fat percentage remained significant factors predicting IGT or diabetes in the OGTT. CONCLUSION: New-onset GC-induced glucose intolerance, even in patients on long-term low-dose treatment, is prevalent despite normal fasting glucose concentration and patients should be screened with an OGTT despite the absence of classic risk factors of diabetes.

Comparison of the analytical and clinical performances of two different routine testing protocols for antinuclear antibody screening.

BACKGROUND: The diagnosis of systemic autoimmune rheumatic diseases (SARD) is based on the detection of serum antinuclear antibodies (ANA) for which indirect immunofluorescence (IIF) is the golden standard. New solid-phase immunoassays have been developed to be used alone or in combination with the detection of extractable antinuclear antibodies (ENA) to improve SARD diagnosis. The purpose of this study was to compare the clinical performances of different ANA screening methods alone or in combination with ENA screening methods for SARD diagnosis. METHODS: A total of 323 patients were screened for ANA by IIF, EliA™ CTD Screen, and ELISA methods. Agreements were calculated between the methods. Then, EliA™ CTD Screen positive samples were screened for ENA by line immunoassay (LIA) and fluorescence enzyme immunoassay (FEIA). RESULTS: The diagnostic accuracy of EliA™ CTD Screen (79% sensitivity and 91% specificity) was better than that of ELISA or IIF. The combination of EliA™ CTD plus IIF had the highest sensitivity (93%). ENA determination revealed that Ro52 and Ro60 were the most prevalent specificities. The use of IIF alone was not able of detecting up to 36% of samples positive for Ro52, and 41% for Ro60. CONCLUSIONS: EliA™ CTD Screen has a better diagnostic performance when compared to IIF and ELISA. The combined use of EliA™ CTD Screen and IIF clearly improves the rate and accuracy of SARD diagnosis. The use of EliA™ CTD Screen as first-line screening technique allows the detection of antibodies, which could not be detected by IIF alone.

Adiponectin Deregulation in Systemic Autoimmune Rheumatic Diseases.

Deregulation of adiponectin is found in systemic autoimmune rheumatic diseases (SARDs). Its expression is downregulated by various inflammatory mediators, but paradoxically, elevated serum levels are present in SARDs with high inflammatory components, such as rheumatoid arthritis and systemic lupus erythematosus. Circulating adiponectin is positively associated with radiographic progression in rheumatoid arthritis as well as with cardiovascular risks and lupus nephritis in systemic lupus erythematosus. However, in SARDs with less prominent inflammation, such as systemic sclerosis, adiponectin levels are low and correlate negatively with disease activity. Regulators of adiponectin gene expression (PPAR-γ, Id3, ATF3, and SIRT1) and inflammatory cytokines (interleukin 6 and tumor necrosis factor α) are differentially expressed in SARDs and could therefore influence total adiponectin levels. In addition, anti-inflammatory therapy could also have an impact, as tocilizumab treatment is associated with increased serum adiponectin. However, anti-tumor necrosis factor α treatment does not seem to affect its levels. Our review provides an overview of studies on adiponectin levels in the bloodstream and other biological samples from SARD patients and presents some possible explanations why adiponectin is deregulated in the context of therapy and gene regulation.

Serum immunoglobulin free light chain levels in systemic autoimmune rheumatic diseases.

Several reports have highlighted the abnormal increments of serum immunoglobulin free light chains (FLCs) in the course of systemic autoimmune rheumatic diseases (SARD), but a comparative analysis among different conditions is still lacking. A strong association between elevated FLC and hepatitis C virus (HCV)-related mixed cryoglobulinaemia (HCVMC) has been well established. Here, we aimed to analyse serum FLC levels in patients with four different SARD in comparison with HCVMC. Using a turbidimetric assay, free κ and λ chains were quantified in sera from 198 SARD patients (37 rheumatoid arthritis, RA; 47 systemic lupus erythematosus, SLE; 52 anti-phospholipid syndrome, APS; 62 primary Sjogren's syndrome, pSS), 62 HCVMC and 50 healthy blood donors (HD). All patient groups showed increased κ levels when compared to HD: 33·5 ± 2·6 mg/l in HCVMC, 26·7 ± 2·3 mg/l in RA, 29·7 ± 1·9 mg/l in SLE, 23·8 ± 1·1 mg/l in APS, 24·2 ± 1·1 mg/l in pSS; 10·1 ± 0·6 mg/l in HD. Free λ levels displayed a significant increase only for HCVMC (20·4 ± 1·4 mg/l) and SLE (18·4 ± 1·0 mg/l) compared to HD (13·6 ± 0·9 mg/l). The increase of κ compared to λ takes into account a κ /λ ratio of 1·6 for all groups. Our results substantially analyse and strengthen the association between FLC and SARD focusing the questions regarding their role in the pathogenesis and diagnosis of human diseases. Unfortunately, the biochemical differences distinguishing normal from pathological FLC have not been identified. Production of different isotypes is probably connected to still-unknown pathways.

The role of biochemical markers of joint tissue remodelling to predict progression and treatment efficacy in inflammatory rheumatic diseases.

Structural damage is a hallmark in RA, spondyloarthropy (SpA) and psoriatric arthritis (PsA). Its progression is difficult to predict and current radiological or inflammatory biological markers lack sensitivity. Biochemical markers of bone, cartilage and synovial tissues provide a dynamic indication of the anabolism and catabolism of joint tissues and can be easily measured by immunoassays. Novel biochemical markers including post-translational modifications of matrix proteins and enzyme-generated neoepitopes with increased tissue and/or biological pathway specificity have been developed. Their evaluation in clinical trials of novel biologic therapies and epidemiological studies indicated that their measurements could be useful to predict progression of structural damage and treatment efficacy, independently of current clinical, radiological and biological indices of disease activity. In this paper we briefly describe the latest developments in biochemical markers and critically analyse the clinical data assessing the utility of established and novel biochemical markers in RA, SpA and PsA.

Acromegaly and joint pain: is there something more? A cross-sectional study to evaluate rheumatic disorders in growth hormone secreting tumor patients.

PURPOSE: The aim of the present study was to evaluate the rheumatic profile in acromegalic patients to better characterize joint pain. METHODS: The immunological pattern (rheumatoid factor; antinuclear antibodies-ANA, extractable nuclear antigens-ENA-Ab; anti-citrullinated protein antibodies; erythrocyte sedimentation rate) was evaluated in 20 acromegaly subjects (AS) and 20 control subjects (CS). Bilateral joint ultrasound of hands/wrists and nail capillaroscopy were also performed. RESULTS: Articular pain was more frequent in AS than in CS (p = 0.027). No difference was detected in immunological parameters. ANA and ENA-Ab were positive in only 10% of AS and in 5% of CS, while no difference was found in anti-citrullinated protein antibodies. No difference was detected between rheumatoid factor positivity, but threefold higher IgG were detected in AS compared to CS. The erythrocyte sedimentation rate was significantly higher in AS than CS (p = 0.040), while in AS, there was a trend in increased Power Doppler (PWD) articular uptake. The capillaroscopic evaluation showed a significant difference in almost each parameter (presence and number of tortuous capillaries, capillary enlargements, and hemorrhages), showing a moderate-to-severe microangiopathy in AS. CONCLUSION: The results of our study suggest that joint damage in acromegaly has not an autoimmune etiology. Increased erythrocyte sedimentation rate levels and PWD alteration in acromegalic population reflect a possible inflammatory nature, while the capillaroscopic findings suggest a moderate-to-severe microangiopathy that could help to identify patients with a greater macroangiopathic risk.

Analysis of antinuclear antibody titers and patterns by using HEp-2 and primate liver tissue substrate indirect immunofluorescence assay in patients with systemic autoimmune rheumatic diseases.

BACKGROUND: Indirect immunofluorescence assay (IIFA) is viewed as a preliminary standard to assess antinuclear antibodies (ANAs). Our aim was to explore ANA positivity rate, titers, and patterns in patients with systemic autoimmune rheumatic diseases (SARD), including systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), primary Sjögren's syndrome (pSS), systemic sclerosis (SSc), and mixed connective tissue disease (MCTD), compared with healthy controls (HC). METHODS: Assess antinuclear antibody titers and patterns were retrospectively identified and compared by IIFA using human epithelial cells (HEp-2) and primate liver tissue substrate according to international consensus in SARD. Serum complement 3 (C3), C4, and immunoglobulin G were compared among subgroups with different ANA titers. The positive predictive values (PPV) for different ANA titers were calculated. RESULTS: There were a total of 3510 samples, including 2034 SLE, 973 RA, 155 SSc, 309 pSS, and 39 MCTD cases. There was no difference in age between HC and SARD, excluding RA. ANA positivity rate in SARD and HC was 78.7% and 12.2%, respectively. A titer of ≥1:320 revealed a PPV of 84.0% in SARD. SLE patients with ANA titers ≥1:320 had significantly lower levels of C3 and C4. AC-4 (31.2%) was the major pattern in patients with SARD, followed by AC-5 (23.9%) and AC-1 (18.8%). SLE mostly presented with AC-4 (30.3%). Several mixed patterns provided a significant hint for SSc and SLE. The major pattern in HC was AC-2 (12.2%). CONCLUSIONS: Assess antinuclear antibody positivity, titers, and patterns display differences in various SARD, contributing to the classification of SARD.

[Antinuclear antibodies in the diagnostics of rheumatic diseases]. / Antinukleäre Antikörper in der Diagnostik rheumatischer Erkrankungen.

Testing for antinuclear antibodies (ANA) on human epithelial cell lines (HEp-2) using indirect immunofluorescence (IIF) is central for ruling out or for diagnosing connective tissue diseases and other diseases, such as primary biliary cholangitis and autoimmune hepatitis as well as drug-induced ANA. The comprehensive description of 29 different ANA-IIF patterns by the international consensus of ANA patterns (ICAP) facilitates the harmonization of ANA-IIF diagnostics. Positive ANA tests are frequently observed in healthy individuals and a reason for referral to rheumatologists. In these cases, the detection of anti-DFS70 antibodies can be helpful to exclude systemic autoimmune rheumatic diseases.

Risk factors for cytomegalovirus disease with cytomegalovirus re-activation in patients with rheumatic disease.

Objective: To assess risk factors for cytomegalovirus (CMV) disease with CMV re-activation in patients with rheumatic disease.Methods: The clinical data of consecutive patients with rheumatic disease who experienced CMV re-activation were examined. We evaluated the difference in various baseline factors at the first detection of CMV pp65 antigenemia on the development of CMV disease using logistic regression models. The changes of laboratory data in the 4 weeks before CMV re-activation were also assessed.Results: We identified 80 patients (median age [interquartile range] = 65.0 years [51.5-74.0]) with CMV re-activation. Oral candidiasis, serum albumin ≤30 g/L, and CMV pp65-positive cell count >5.6/105 polymorphonuclear leukocyte cells were found to be associated with CMV disease (odds ratio [OR] [95% CI] = 9.99 [2.02-49.50], 11.4 [1.94-67.40] and 6.80 [1.63-28.30], respectively). Moreover, decreases in serum albumin level and blood lymphocyte count in the 4 weeks before CMV re-activation also predicted CMV disease (OR [95% CI] = 2.02 [1.07-3.8] and 1.96 [1.09-3.54], respectively).Conclusion: In CMV re-activation patients with rheumatic disease, the presence of oral candidiasis, high CMV pp65 positive cell count, and hypoalbuminemia are possible risk factors for CMV disease.

Methods for type I interferon detection and their relevance for clinical utility and improved understanding of rheumatic diseases.

Type I interferons (IFN) are a class of inducible and protective cytokines best known for immune defence against viruses and intracellular bacteria. Inappropriate stimulation or defective negative regulation of type I IFN expression however can lead to persistent type I IFN activity with detrimental effects. This is particularly relevant for a class of monogenic autoinflammatory diseases ("type I interferonopathies"), along with many other complex rheumatic diseases such as systemic lupus erythematosus (SLE), dermatomyositis (DM), systemic sclerosis (SSc), rheumatoid arthritis (RA) and Sjögren's syndrome (SS). Direct detection of type I interferon protein in biologic samples has proved challenging, thus indirect methods are often used to infer the presence of type I IFN via quantification of antiviral activity and/or induced expression of IFN-responsive genes. While some of these methods have been used to inform clinical care, none have proven feasible for everyday clinical practice. However, with new technologies emerging, this may soon change. This review provides a brief summary of the available methods to gauge the presence of type I IFN and their application for the improved understanding, diagnosis and monitoring of type I interferonopathies and other rheumatic diseases.

Serum uric acid increases in patients with systemic autoimmune rheumatic diseases after 3 months of treatment with TNF inhibitors.

In patients with gout, the serum uric acid (SUA) is usually lower during acute gouty attacks than during intercritical periods. It has been suggested that systemic inflammatory response can cause this phenomenon. The objective is to determine whether therapy with TNF inhibitors (TNFis) affects SUA levels in patients with systemic autoimmune rheumatic diseases (SARDs) and whether SUA changes correlate with pro-inflammatory cytokines or with the oxidative stress marker allantoin. In this study, SUA, CRP, creatinine, MCP-1, IFN-α2, IFN-γ, Il-1ß, IL-6, IL-8, IL-10, IL-12, IL-17a, IL-18, IL-23, IL-33, TNF-α, and allantoin levels were measured prior to and after 3 months of TNFis treatment in patients with SARDs. The values obtained in the biochemical assays were then tested for associations with the patients' demographic and disease-related data. A total of 128 patients (rheumatoid arthritis, n = 44; ankylosing spondylitis, n = 45; psoriatic arthritis, n = 23; and adults with juvenile idiopathic arthritis, n = 16) participated in this study. Among the entire patient population, SUA levels significantly increased 3 months after starting treatment with TNFis (279.5 [84.0] vs. 299.0 [102.0] µmol/l, p < 0.0001), while the levels of CRP, IL-6, IL-8, and MCP-1 significantly decreased. Male sex was the most powerful baseline predictor of ΔSUA in univariate and multivariate models. None of the measured laboratory-based parameters had statistically significant effects on the magnitude of ΔSUA. 3 months of anti-TNF therapy increased the levels of SUA in patients with SARDs, but neither the measured pro-inflammatory cytokines nor the oxidation to allantoin appeared responsible for this effect.

Hydroxychloroquine: balancing the need to maintain therapeutic levels with ocular safety: an update.

PURPOSE OF REVIEW: Antimalarial drugs including chloroquine, its less toxic quinolone-derivative hydroxychloroquine (HCQ), and quinacrine have become cornerstones in the treatment of autoimmune diseases including systemic lupus, rheumatoid arthritis, sarcoidosis, and Sjogren syndrome; cutaneous disorders, antiphospholipid syndrome, and have recently been employed at higher dioses in oncology. Benefits include anti-inflammatory effects, protection against thrombosis, and improved control of hyperglycemia and hyperlipidemia. In general, both the therapeutic advantages and the toxic effects of the drugs correlate with the dose and the duration of therapy. Here we summarize the current literature regarding the administration and the safety profile of HCQ in management of rheumatologic disease and focus on the most recent revised American Academy of Ophthalmology (AAO) guidelines for prevention and detection of hydroxychloroquine retinopathy to help guide therapeutic decision-making for patients. RECENT FINDINGS: The risk of antimalarial-induced retinal toxicity is better predicted by calculating the daily dosage based on 5 mg/kg total body weight rather than 6.5 mg/kg lean body weight and reducing dosage in patients with risk factors such as renal failure. The risk of retinal toxicity after 5 years is substantially increased even when these guidelines are followed; hence dose reduction is appropriate with long-term use. Newer techniques provide improved detection of early signs of retinal damage. These advances are reflected in the revised AAO guidelines 2016, which are in part based on the retrospective study by Melles and Marmor of HCQ toxicity. SUMMARY: The most important changes in practice guidelines include dose calculation based on total body weight, dose reduction after long-term use, and intensified screening with techniques including optical coherence tomography (OCT) after 5 years.

Results, meta-analysis and a first evaluation of UNOxR, the urinary nitrate-to-nitrite molar ratio, as a measure of nitrite reabsorption in experimental and clinical settings.

We recently found that renal carbonic anhydrase (CA) is involved in the reabsorption of inorganic nitrite (NO2-), an abundant reservoir of nitric oxide (NO) in tissues and cells. Impaired NO synthesis in the endothelium and decreased NO bioavailability in the circulation are considered major contributors to the development and progression of renal and cardiovascular diseases in different conditions including diabetes. Isolated human and bovine erythrocytic CAII and CAIV can convert nitrite to nitrous acid (HONO) and its anhydride N2O3 which, in the presence of thiols (RSH), are further converted to S-nitrosothiols (RSNO) and NO. Thus, CA may be responsible both for the homeostasis of nitrite and for its bioactivation to RSNO/NO. We hypothesized that enhanced excretion of nitrite in the urine may contribute to NO-related dysfunctions in the renal and cardiovascular systems, and proposed the urinary nitrate-to-nitrite molar ratio, i.e., UNOxR, as a measure of renal CA-dependent excretion of nitrite. Based on results from clinical and experimental animal studies, here, we report on a first evaluation of UNOxR. We determined UNOxR values in preterm neonates, healthy children, and adults, in children suffering from type 1 diabetes mellitus (T1DM) or Duchenne muscular dystrophy (DMD), in elderly subjects suffering from chronic rheumatic diseases, type 2 diabetes mellitus (T2DM), coronary artery disease (CAD), or peripheral arterial occlusive disease (PAOD). We also determined UNOxR values in healthy young men who ingested isosorbide dinitrate (ISDN), pentaerythrityl tetranitrate (PETN), or inorganic nitrate. In addition, we tested the utility of UNOxR in two animal models, i.e., the LEW.1AR1-iddm rat, an animal model of human T1DM, and the APOE*3-Leiden.CETP mice, a model of human dyslipidemia. Mean UNOxR values were lower in adult patients with rheumatic diseases (187) and in T2DM patients of the DALI study (74) as compared to healthy elderly adults (660) and healthy young men (1500). The intra- and inter-variabilities of UNOxR were of the order of 50% in young and elderly healthy subjects. UNOxR values were lower in black compared to white boys (314 vs. 483, P = 0.007), which is in line with reported lower NO bioavailability in black ethnicity. Mean UNOxR values were lower in DMD (424) compared to healthy (730) children, but they were higher in T1DM children (1192). ISDN (3 × 30 mg) decreased stronger UNOxR compared to PETN (3 × 80 mg) after 1 day (P = 0.046) and after 5 days (P = 0.0016) of oral administration of therapeutically equivalent doses. In healthy young men who ingested NaNO3 (0.1 mmol/kg/d), UNOxR was higher than in those who ingested the same dose of NaCl (1709 vs. 369). In LEW.1AR1-iddm rats, mean UNOxR values were lower than in healthy rats (198 vs. 308) and comparable to those in APOE*3-Leiden.CETP mice (151).

Prevalence of anti-DFS70 antibodies in patients with and without systemic autoimmune rheumatic diseases.

OBJECTIVES: Autoantibodies to the dense fine speckled 70 (DFS70) antigen are common among antinuclear antibodies (ANA) positive healthy individuals (HI). We assessed the prevalence of anti-DFS70 antibodies in patients with and without ANA-associated rheumatic diseases (AARDs) by two methods: chemiluminescent immunoassay (CIA) and an indirect immunofluorescence (IIF) assay based on immunoadsorption for DFS70. METHODS: Fifty-one ANA-positive sera samples from patients with confirmed clinical diagnosis of AARD, 92 samples from HI and 85 samples submitted to a reference laboratory for routine ANA testing were evaluated for the presence of anti-DFS70 antibodies. The samples were evaluated by QUANTA Flash DFS70 CIA using BIO-FLASH instrument and by NOVA Lite selected HEp-2 kit on NOVA View - an automated IIF system. Sera with DFS positive pattern were pre-absorbed with highly purified human DFS70 antigen, and then tested again. RESULTS: Twenty-four samples (10.5%) tested by QUANTA Flash DFS70 CIA were positive for anti-DFS70 antibodies. The prevalence of monospecific anti-DFS70 antibodies was significantly higher in healthy subjects than in patients with AARDs (10.9% vs. 1.9%, p=0.02). The frequency of anti-DFS70 antibodies in samples submitted for routine ANA testing was 15.2%. A very good agreement was found between CIA and the DFS pattern identified by the automated HEp-2 IIF (kappa=0.97). In 80% of the samples obtained from patients without AARDs, immunoadsorption effectively inhibited the anti-DFS70 antibodies. CONCLUSIONS: The data confirm that mono-specific anti-DFS70 antibodies are a strong discriminator between ANA positive HI and AARD patients, and their evaluation should be included in ANA testing algorithms.