Treatment experiences with focus on IL-6R inhibition in patients with VEXAS-syndrome and a case of remission with azacytidine treatment.

OBJECTIVES: The aim of the study was to evaluate the treatment response to Interleukin-6-receptor inhibitition (IL-6Ri), primarily tocilizumab, in patients with VEXAS. METHODS: Data were obtained from review of hospital based clinical records and included symptoms, laboratory data, transfusion history, pathology reports, imaging, and treatment. RESULTS: Fifteen patients were treated with tocilizumab intravenously. Two patients changed treatment to subcutaneous sarilumab. Three discontinued treatment due to treatment failure.Of the 10 patients with treatment-response and prednisone use prior to IL-6Ri one was tapered off prednisone, one used it intermittently, and seven patients could be reduced to 10 mg or less daily.Three patients exhibited a marked decrease in UBA1-levels during IL-6Ri which corresponded with symptom control and normalization of haemoglobin levels. However, in most a progressive marrow failure occurred as indicated by decreasing platelet levels, increasing MCV, and for some, declining haemoglobin levels and transfusion dependence in spite of control of the inflammatory symptoms and low c-reactive protein levels.One patient became refractory to both tocilizumab and sarilumab, and had previously failed conventional DMARDs, JAK-inhibition, TNFa-inhibition, and interleukin-1R-inhibiton. Treatment with 9 cycles of azacytidine resulted in complete symptom remission, discontinuation of prednisone, normalization of biochemical parameters and undetectable UBA1 mutation levels which has now lasted for 10 months since cessation of azacytidine. CONCLUSION: IL-6Ri induces control of inflammatory symptoms and allows decreased prednisone usage in a large subset of VEXAS patients. However, most experience progressive bone marrow failure during IL-6Ri.Azacytidine could be a promising treatment strategy and warrants further investigation.

Polyautoimmunity in patients with cutaneous lupus erythematosus: A nationwide sex- and age-matched cohort study from Denmark.

Background: Polyautoimmunity is defined as having 2 or more autoimmune diseases. Little is known about polyautoimmunity in patients with cutaneous lupus erythematosus (CLE). Objectives: To estimate prevalence and 5-year incidence of non-lupus erythematosus (LE) autoimmune diseases in patients with CLE. Methods: Patients with CLE were identified In the Danish National Patient Registry and each patient was age- and sex-matched with 10 general population controls. Outcome information on non-LE autoimmune diseases was obtained by register-linkage between Danish National Patient Registry and the National Prescription Register. The risk ratio (RR) for prevalent non-LE autoimmune disease at time of CLE diagnosis was calculated in modified Poisson regression; and hazard ratios (HRs) for incident non-LE autoimmune disease were estimated in Cox regression analyses. Results: Overall, 1674 patients with CLE had a higher prevalence of a non-LE autoimmune disease than the comparators (18.5 vs 7.9%; RR 2.4; 95% CI, 2.1 to 2.6). Correspondingly, the cumulative incidence of a non-LE autoimmune disease during 5 years of follow-up was increased for the patients with CLE: HR 3.5 (95% CI, 3.0 to 4.0). Limitations: Risk of detection and misclassification bias, mainly pertaining to the CLE group. Conclusion: Patients with CLE had higher prevalence and 5-year cumulative incidence of a non-LE autoimmune disease than the general population.

Myositis-related autoantibody profile and clinical characteristics stratified by anti-cytosolic 5'-nucleotidase 1A status in connective tissue diseases.

INTRODUCTION/AIMS: Cytosolic 5'-nucleotidase 1A (cN-1A) autoantibodies have been recognized as myositis-related autoantibodies. However, their correlations with clinical characteristics and other myositis-specific and myositis-associated autoantibodies (MSAs/MAAs) are still unclear. We aimed to establish the prevalence and clinical and laboratory associations of cN-1A autoantibodies in a cohort of patients with connective tissue diseases. METHODS: A total of 567 participants (182 idiopathic inflammatory myopathies [IIM], 164 systemic lupus erythematosus [SLE], 121 systemic sclerosis [SSc], and 100 blood donors [BD]) were tested for the presence of cN-1A autoantibodies and other myositis-specific and myositis-associated autoantibodies (MSAs/MAAs). Clinical and laboratory characteristics were compared between anti-cN-1A positive and negative patients with sporadic inclusion body myositis (sIBM) and between anti-cN-1A positive and negative patients with non-IBM IIM. RESULTS: In the sIBM cohort, 30 patients (46.9%) were anti-cN-1A positive vs. 18 (15.2%) in the non-IBM IIM cohort, 17 (10%) were anti-cN-1A positive in the SLE cohort and none in the SSc or the BD cohorts. Anti-cN-1A positivity had an overall sensitivity of 46.9% and a specificity of 93.2% for sIBM. Dysphagia was more frequent in the anti-cN-1A positive vs. negative sIBM patients (p = .04). In the non-IBM IIM group, being anti-cN-1A antibody positive was associated with the diagnosis polymyositis (p = .04) and overlap-myositis (p = .04) and less disease damage evaluated by physician global damage score (p < .001). DISCUSSION: cN-1A autoantibodies were predominantly found in IIM patients and was associated with dysphagia in sIBM patients. Notably, anti-cN-1A appears to identify a distinct phenotype of anti-cN-1A positive non-IBM IIM patients with a milder disease course.

Elevated Antibody Titers to Epstein-Barr Virus and Cytomegalovirus in Patients with Drug-Induced Lupus.

Systemic lupus erythematosus (SLE) is an autoimmune disease, which has been associated with Epstein-Barr virus (EBV) and Cytomegalovirus (CMV) infection. Drug-induced lupus (DIL) is a lupus-like disease caused by the intake of therapeutic drugs, which has been estimated to cause approximately 10-15% of lupus-like cases. Although SLE and DIL share common clinical symptoms, there are some fundamental differences between DIL and SLE onset. Moreover, it remains to be examined whether environmental factors, such as EBV and CMV infections, may contribute to the development of DIL. This study focused on examining the possible association between DIL and EBV and CMV infections, by examining IgG titers to EBV and CMV antigens in serum samples by enzyme-linked immunosorbent assays. Antibody titers to EBV early antigen-diffuse and CMV pp52 were found to be significantly elevated in both SLE and DIL patients compared to healthy controls, although no correlation was found for antibodies to the two virus antigens in the respective disease groups. Moreover, total IgG titers were reduced in SLE and DIL serum samples, which may reflect a general lymphocytopenia, which commonly is associated with SLE. The current findings support that EBV and CMV infections may contribute to the development of DIL and that onset of both diseases are related.

Opioids in the Treatment of Chronic Idiopathic Diarrhea in Humans-A Systematic Review and Treatment Guideline.

In patients with chronic idiopathic diarrhea resistant to standard treatment, opioids are often used as rescue therapy. This systematic review investigated opioid effects on gut function in chronic diarrhea. PubMed and Embase were searched regarding effects of opioid agonists on the gastrointestinal tract in humans with chronic or experimentally induced diarrhea. A total of 1472 relevant articles were identified and, after thorough evaluation, 11 clinical trials were included. Generally, studies reported a reduction in stool frequency and an increase in transit time during treatment with the opioid receptor agonists loperamide, asimadoline, casokefamide, and codeine compared with placebo. Loperamide and diphenoxylate significantly improved stool consistency compared with placebo, whereas asimadoline showed no such effects. Compared with placebo, loperamide treatment caused less abdominal pain and urgency. Asimadoline showed no significant subjective improvements, but fedotozine was superior to placebo in reducing abdominal pain and bloating in selected patients. Only two relevant studies were published within the last 20 years, and standardized endpoint measures are lacking. Most trials included few participants, and further evidence is needed from larger, prospective studies. Likewise, consensus is needed to standardize endpoints for stool frequency, transit time, and consistency to conduct future meta-analyses on opioids in management of chronic idiopathic diarrhea.

A cluster of type II interferon-regulated genes associates with disease activity in patients with systemic lupus erythematosus.

Upregulation of interferon-regulated genes (IRGs), denoted IFN signature, in peripheral blood has been used as an indirect measure of IFN pathway activation in patients with systemic lupus erythematosus (SLE). However, it has not been determined, which IFN signatures that optimally reflect clinical disease activity. In this study, we determined an IFN signature based on the expression of 128 IRGs in whole blood from 34 SLE patients in a cross-sectional (CS) study, 11 with active lupus nephritis followed longitudinally (LS) and 15 healthy controls. Blood samples were collected in PAXgene tubes and RNA was extracted and purified using a PAXgene blood RNA kit (Qiagen). Gene expression was measured using the NanoString nCounter Gene Expression platform. The CS SLE patients with higher disease activity displayed thrice as many upregulated IRGs (n = 46) as the rest. These IRGs clustered in three groups, consisting of IRGs known to be predominantly stimulated by type I (gene cluster K1) and type II (gene clusters K2 and 3) IFNs. SLEDAI-2K scores associated with the K2 and K3 gene scores (ß = 0.372 and ß = 0.419, both p < 0.015) but not with K1. In the longitudinal study, the mean SLEDAI-2K score decreased after an average follow-up of 360 days (ß = -2.08, P = 5.09 × 10-12). The mean K1, K2 and K3 gene scores did not change over time, however longitudinal changes in SLEDAI-2K and K3 scores were associated (ß = 0.814, p = 0.007). This study validates the presence of type I IRG subsets that do not associate with disease activity in SLE patients. The novel finding in this study is the association between a type II IRG subset and disease activity. Both findings may have significant implications for choosing IRGs defining clinically relevant IFN signatures.

Gender- and age-specific rates of heart failure and other adverse cardiovascular outcomes in systemic sclerosis.

OBJECTIVE: To investigate the long-term rates of heart failure (HF) and other adverse cardiovascular outcomes, including arrhythmias, myocardial infarction, ischaemic stroke, venous thromboembolism, pulmonary hypertension and pericarditis, in SSc patients according to gender and age. METHODS: Using Danish nationwide registries, SSc patients (diagnosed from 1996 to 2018) were matched with four controls from the background population by gender, age and comorbidities. Cox regression was used to compare the rates of cardiovascular outcomes between SSc patients and controls and the rate of mortality between SSc patients developing HF and HF patients without SSc, according to gender and age (above/below median). RESULTS: In total, 1569 SSc patients were matched with 6276 non-SSc controls (median age 55 years, 80.4% women, median follow-up 7.3 years). SSc had a higher rate of HF in both women [HR 2.99 (95% CI 2.18, 4.09)] and men [HR 3.01 (1.83, 4.95)] (Pinteraction = 0.88), with similar trends for other cardiovascular outcomes. SSc had a higher rate of HF in patients <55 years of age [HR 4.14 (95% CI 2.54, 6.74)] and ≥55 years [HR 2.74 (1.98, 3.78)] (Pinteraction = 0.22), with similar trends for other cardiovascular outcomes. SSc patients with new-onset HF had a higher rate of mortality than HF patients without a history of SSc, irrespective of gender (Pinteraction = 0.53) and age (Pinteraction = 0.43). CONCLUSIONS: SSc was associated with higher rates of HF and other cardiovascular outcomes than matched controls, irrespective of gender and age. Among patients with new-onset HF, a history of SSc was associated with higher mortality.

Neuromodulation of somatosensory pain thresholds of the neck musculature using a novel transcranial direct current stimulation montage: a randomized double-blind, sham controlled study.

OBJECTIVES: Anodal transcranial direct current stimulation (tDCS) of primary motor cortex (M1) and cathodal of the primary sensory cortex (S1) have previously shown to modulate the sensory thresholds when administered with the reference electrode located over the contralateral supraorbital area (SO). Combining the two stimulation paradigms into one with simultaneous stimulation of the two brain areas (M1 + S1 - tDCS) may result in a synergistic effect inducing a prominent neuromodulation, noticeable in the pain thresholds. The aim of this study is to assess the efficacy of the novel M1 + S1 - tDCS montage compared to sham-stimulation in modulating the pain thresholds in healthy adults. METHODS: Thirty-nine (20 males) subjects were randomly assigned to either receiving 20 min. active M1 + S1 - tDCS or sham tDCS in a double-blinded single session study. Thermal and mechanical pain thresholds were assessed before and after the intervention. RESULTS: There were no significant differences in the pain thresholds within either group, or between the M1 + S1 - tDCS group and the Sham-tDCS group (p>0.05), indicating that the intervention was ineffective in inducing a neuromodulation of the somatosensory system. CONCLUSIONS: Experimental investigations of novel tDCS electrode montages, that are scientifically based on existing studies or computational modelling, are essential to establish better tDCS protocols. Here simultaneous transcranial direct current stimulation of the primary motor cortex and primary sensory cortex showed no effect on the pain thresholds of the neck musculature in healthy subjects. This tDCS montage may have been ineffective due to how the electrical field reaches the targeted neurons, or may have been limited by the design of a single tDCS administration. The study adds to the existing literature of the studies investigating effects of new tDCS montages with the aim of establishing novel non-invasive brain stimulation interventions for chronic neck pain rehabilitation. North Denmark Region Committee on Health Research Ethics (VN-20180085) ClinicalTrials.gov (NCT04658485).

Systematic review of the nuclear factor erythroid 2-related factor 2 (NRF2) system in human chronic kidney disease: alterations, interventions and relation to morbidity.

BACKGROUND: Nuclear factor erythroid 2-related factor 2 (NRF2) and its effectors NAD(P)H:quinoneoxidoreductase 1 (NQO1) and haem oxygenase 1 (HO-1) are of interest in kidney disease. We therefore reviewed studies about their status in patients with chronic kidney disease (CKD). METHODS: We undertook systematic searches of PubMed and Excerpta Medica dataBASE (EMBASE) databases. Alterations of NRF2, NQO1 and HO-1 in CKD, their responses to interventions and their relation to clinically relevant parameters were reported. RESULTS: We identified 1373 articles, of which 32 studies met the inclusion criteria. NRF2 levels were decreased in the majority of analyses of CKD patients. Half of the analyses showed a similar or increased NQO1 level versus control, whereas in half of the analyses NQO1 was decreased. Most of the studies reported either an increased or similar HO-1 level in CKD patients compared with controls. For patients with CKD Stages 1-4, studies reported positive correlations to markers of kidney disease severity. Also, positive associations of NQO1/HO-1 levels to inflammation and comorbidities were reported. One-third of the studies showed discordant changes between gene expression and protein level of NRF2 system components. Two-thirds of intervention studies (50% dietary, such as using resistant starch) reported an increase of NRF2, NQO1 or HO-1. CONCLUSIONS: In patients with CKD, NRF2 expression was downregulated, while NQO1 and HO-1 showed varying alterations related to inflammation, comorbidities and severity of kidney damage. Interventions that increased NRF2 system components were described, but their effectiveness and clinical relevance require further clinical studies of high quality. Research on gene expression together with protein analyses is indispensable to understand NRF2 system alterations in CKD.

Human herpesvirus infections and circulating microvesicles expressing galectin-3 binding protein in patients with systemic lupus erythematosus.

OBJECTIVES: Circulating microvesicles (MVs) expressing the type 1 interferon-inducible protein galectin-3 binding protein (G3BP) are potentially major sources of autoantigens in systemic lupus erythematosus (SLE). In this study, we explore if plasma concentrations of G3BP-expressing MVs correlate with signs of various active human herpesvirus (HHV) infections in SLE patients, suggesting a virus-induced mechanism for the generation of these vesicles. METHODS: In 49 SLE patients, the plasma levels of immunoglobulin G (IgG) against cytomegalovirus (CMV) pp52, Epstein-Barr virus (EBV) early antigen diffuse (EA/D), and HHV6 p41 were measured by ELISAs and used as humoral markers of ongoing/recently active viral infection. MVs in platelet-poor plasma were quantified and characterised by flow cytometry, with regard to the binding of Annexin V (AnxV) and the expression of G3BP. Spearman's rho and the Wilcoxon rank-sum test were applied for associative evaluation of virus serology with MV subsets, and clinical and demographic data. RESULTS: The CMV pp52-directed antibodies correlated positively with the high G3BP-expressing MVs; either low (rho=0.4, p-value=0.005) or high (rho=0.37, p-value=0.01) in AnxV-expression. Furthermore, these MV subsets were higher in individuals with high and low IgG levels against CMV pp52 and EBV EA/D, respectively, relative to subjects with low and high IgG levels against these HHV antigens. Importantly, none of the associations were explained by immunosuppressants or antimalarials. CONCLUSIONS: Ongoing/recently active CMV infection is associated with circulating MVs expressing G3BP in SLE patients, supporting a link between specific viral infections and potentially pathogenic MVs in SLE.

The Collagen Receptor uPARAP in Malignant Mesothelioma: A Potential Diagnostic Marker and Therapeutic Target.

Malignant mesothelioma (MM) is a highly aggressive cancer with limited therapeutic options. We have previously shown that the endocytic collagen receptor, uPARAP, is upregulated in certain cancers and can be therapeutically targeted. Public RNA expression data display uPARAP overexpression in MM. Thus, to evaluate its potential use in diagnostics and therapy, we quantified uPARAP expression by immunohistochemical H-score in formalin-fixed paraffin-embedded bioptic/surgical human tissue samples and tissue microarrays. We detected pronounced upregulation of uPARAP in the three main MM subtypes compared to non-malignant reactive mesothelial proliferations, with higher expression in sarcomatoid and biphasic than in epithelioid MM. The upregulation appeared to be independent of patients' asbestos exposure and unaffected after chemotherapy. Using immunoblotting, we demonstrated high expression of uPARAP in MM cell lines and no expression in a non-malignant mesothelial cell line. Moreover, we showed the specific internalization of an anti-uPARAP monoclonal antibody by the MM cell lines using flow cytometry-based assays and confocal microscopy. Finally, we demonstrated the sensitivity of these cells towards sub-nanomolar concentrations of an antibody-drug conjugate formed with the uPARAP-directed antibody and a potent cytotoxin that led to efficient, uPARAP-specific eradication of the MM cells. Further studies on patient cohorts and functional preclinical models will fully reveal whether uPARAP could be exploited in diagnostics and therapeutic targeting of MM.

Galectin-3-binding protein is a novel predictor of venous thromboembolism in systemic lupus erythematosus.

OBJECTIVES: Venous (VTE) and arterial (AT) thrombosis in systemic lupus erythematosus (SLE) are poorly explained and difficult to predict. Leptin and tumour necrosis factor-like weak inducer of apoptosis (TWEAK) have been linked to subclinical atherosclerosis and galectin-3-binding protein (G3BP) to type I interferon activation and a pro-thrombotic environment. Thus, we explore serum G3BP, interferon gamma-induced protein 10 (IP-10), soluble CD163 (sCD163), TWEAK and leptin as predictors of VTE and AT, damage accrual, and all-cause mortality during follow-up in a Swedish SLE cohort. METHODS: Baseline data were available from 162 SLE patients. VTE (deep vein thrombosis and/or pulmonary embolism), AT (myocardial infarction and/or stroke), damage accrual, and survival data were the main study outcomes and available at follow-up (median of five years). Baseline serum G3BP, IP-10, sCD163, TWEAK and leptin were measured and analysed by univariable and multivariable methods for association to the study outcomes. RESULTS: During the follow-up, 10 (6%) VTE and 13 (8%) AT events occurred. The SLICC/ACR Damage Index increased in 78 (48%) patients, and 19 (12%) patients died. In the univariable regression analysis G3BP levels were significantly associated with an increased risk of VTE (hazard ratio (HR) 1.11, 95% confidence interval (CI): 1.01-1.22, p=0.03). This persisted in the adjusted multivariable analyses (HR 1.18, 95% CI: 1.05-1.33, p=0.007). The other biomarkers were not associated with AT/VTE, damage accrual, or all-cause mortality. CONCLUSIONS: Our study identifies serum G3BP as a novel predictor of VTE in SLE. Further studies are needed to understand the role of G3BP in VTE and translate this into clinical practice.

Role of Neutrophil Extracellular Traps Regarding Patients at Risk of Increased Disease Activity and Cardiovascular Comorbidity in Systemic Lupus Erythematosus.

OBJECTIVE: Neutrophil extracellular traps (NET) are essential in host defense, but are also linked to inflammation and autoimmunity, including in systemic lupus erythematosus (SLE). We recently described that immune complexes (IC) induce NET formation, promoting SLE-like disease in mice. In the current study, we investigated, for the first time to our knowledge, the role of NET in human SLE and their association with disease activity and severity. METHODS: Levels of NET (myeloperoxidase-DNA complexes) were analyzed in plasma from 4 cross-sectional SLE cohorts (n = 44-142), 1 longitudinal SLE cohort (n = 47), and healthy individuals (n = 100) using ELISA. Type I interferon activity was determined using a cell reporter system. RESULTS: Patients with SLE had elevated levels of NET in circulation compared to healthy controls (p < 0.01). NET levels identified patients with a severe disease phenotype characterized by IC-driven nephritis (p < 0.05). Though not associated with current disease activity (p = 0.20), levels of NET were associated with future increase in the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) within 3 months (OR 1.75, p = 0.01), as well as an overall heightened SLEDAI over 1 year (p < 0.01). Finally, levels of NET were associated with arterial events (OR 5.0, p = 0.02) and endothelial cell activation (p < 0.001). CONCLUSION: NET levels are elevated in patients with SLE, associated with IC-driven disease. NET levels provide significant clinical value in identifying patients at risk of active disease and/or severe disease, including nephritis and cardiovascular disease, and may allow for early interventions.

Stimulation of Mononuclear Cells Through Toll-Like Receptor 9 Induces Release of Microvesicles Expressing Double-Stranded DNA and Galectin 3-Binding Protein in an Interferon-α-Dependent Manner.

Background: Microvesicles (MVs) expressing the type 1 interferon (IFN)-inducible protein galectin-3 binding protein (G3BP) may play a pathogenic role in systemic lupus erythematosus (SLE). Co-expression of double-stranded DNA (dsDNA) on such MVs may render them immunogenic and targets for anti-dsDNA antibodies. Little is known about the mechanisms underlying generation of this MV population. In this study, we investigated how Toll-like receptors (TLRs), IFN-α, and T cells are involved in this process in healthy subjects. Methods: Peripheral blood mononuclear cells (PBMCs) isolated from 12 healthy donors were stimulated in-vitro for 24 h with a series of TLR-agonists or the T cell activating antibody OKT3 or were subjected to apoptosis by incubation with staurosporine. MVs in the supernatants were subsequently isolated by differential centrifugation and were quantified and characterized with respect to expression of G3BP and dsDNA by flow cytometry. Results: Stimulation of PBMCs with the TLR9-agonist and strong IFN-α inducer ODN2395 significantly increased the release of MVs expressing G3BP. The production of MVs with this phenotype was markedly enhanced by co-stimulation of T cells. Furthermore, dependency on IFN-α in the generation of G3BP-expressing MVs was indicated by a marked reduction following addition of the IFN-α inhibitor IFN alpha-IFNAR-IN-1 hydrochloride. Conclusion: Release of G3BP-expressing MVs from healthy donor PBMCs is induced by stimulation of TLR9 in an IFN-α-dependent manner and is enhanced by co-stimulation of T cells.

[Susac syndrome is an important differential diagnosis in monosymptomatic encephalopathy in young adults].

This is a case report of a 29-year-old man, who presented with progressive confusion, memory problems and personality changes during 1.5 months. Later, he developed bilateral hearing impairment but had no visual symptoms. A brain MRI showed numerous small hyperintensities in both hemispheres, a retinal fluorescence angiography revealed multiple hyperfluorescent arterial occlusions, and an audiogram showed bilateral hearing impairment. The patient was treated for Susac syndrome with high-dose corticosteroids initially, followed by intravenous immunoglobulin and cyclophosphamide.

Increased antibody levels to stage-specific Epstein-Barr virus antigens in systemic autoimmune diseases reveal a common pathology.

The immune responses to antigens from different stages of the Epstein-Barr virus (EBV) life cycle were investigated in systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), Sjögren's syndrome (SS), and systemic sclerosis (SSc) to gain knowledge of EBV's involvement in the etiology of systemic autoimmune diseases (SADs) and for an overview of the humoral immune responses against EBV. Investigations were performed by the use of ELISA. IgM, IgA, and IgG antibody binding to 11 EBV antigens: EBNA1, EBNA2, BALF5, EAD, BALF2, EA/R, VCA p18, VCA p23, gB, gp350, and gp42 were examined in serum pools from SAD patients and healthy controls (HCs). Increased antibody levels against the 11 EBV antigens in the SAD pools were seen compared to the HC pool. Specifically, SLE was characterized by strongly increased IgA to EAD both compared to HCs and other SADs, and RA was characterized by increased IgM levels to several EBV antigens. The SADs may be partly distinguished by their differential immune responses to various antigens in the EBV life cycle. All together, these findings support an association between EBV infection and SADs.

Autoantibodies to Cytosolic 5'-Nucleotidase 1A in Primary Sjögren's Syndrome and Systemic Lupus Erythematosus.

Introduction: Autoantibodies to cytosolic 5'-nucleotidase 1A (cN-1A; NT5C1A) have a high specificity when differentiating sporadic inclusion body myositis from polymyositis and dermatomyositis. In primary Sjögren's syndrome (pSS) and systemic lupus erythematosus (SLE) anti-cN-1A autoantibodies can be detected as well. However, various frequencies of anti-cN-1A reactivity have been reported in SLE and pSS, which may at least in part be explained by the different assays used. Here, we determined the occurrence of anti-cN-1A reactivity in a large number of patients with pSS and SLE using one standardized ELISA. Methods: Sera from pSS (n = 193) and SLE patients (n = 252) were collected in five European centers. Anti-cN-1A, anti-Ro52, anti-nucleosome, and anti-dsDNA reactivities were tested by ELISA (Euroimmun AG) in a single laboratory. Correlations of anti-cN-1A reactivity with demographic data and clinical data (duration of disease at the moment of serum sampling, autoimmune comorbidity and presence of muscular symptoms) were analyzed using SPSS software. Results: Anti-cN-1A autoantibodies were found on average in 12% of pSS patients, with varying frequencies among the different cohorts (range: 7-19%). In SLE patients, the anti-cN-1A positivity on average was 10% (range: 6-21%). No relationship was found between anti-cN-1A reactivity and the presence or absence of anti-Ro52, anti-nucleosome, and anti-dsDNA reactivity in both pSS and SLE. No relationship between anti-cN-1A reactivity and duration of disease at the moment of serum sampling and the duration of serum storage was observed. The frequency of muscular symptoms or viral infections did not differ between anti-cN-1A-positive and -negative patients. In both disease groups anti-cN-1A-positive patients suffered more often from other autoimmune diseases than the anti-cN-1A-negative patients (15 versus 5% (p = 0.05) in pSS and 50 versus 30% (p = 0.02) in SLE). Conclusion: Our results confirm the relatively frequent occurrence of anti-cN-1A in pSS and SLE patients and the variation in anti-cN-1A reactivity between independent groups of these patients. The explanation for this variation remains elusive. The correlation between anti-cN-1A reactivity and polyautoimmunity should be evaluated in future studies. We conclude that anti-cN-1A should be classified as a myositis-associated-, not as a myositis-specific-autoantibody based on its frequent presence in SLE and pSS.

Clinical and Serological Associations with the Development of Incident Proteinuria in Danish Patients with Systemic Lupus Erythematosus.

OBJECTIVE: In a longitudinal cohort study, we investigated whether clinical and serological manifestations at the time of classification of systemic lupus erythematosus (SLE) were predictive of subsequent development of incident proteinuria as a biomarker of incident lupus nephritis. METHODS: Patients fulfilling SLE classification criteria but having no proteinuria prior to or at the time of classification were included. Data on SLE manifestations, vital status, criteria-related autoantibodies, and SLE-associated medications were collected during clinical visits and supplemented by chart review. HR were calculated by Cox regression analyses. RESULTS: Out of 850 patients with SLE, 604 had not developed proteinuria at the time of SLE classification. Of these 604 patients, 184 (30%) developed incident proteinuria following SLE classification. The patients had a median followup of 11 years and 7 months. Younger age and history of psychosis at the time of classification were associated with development of incident proteinuria, just as were lymphopenia (HR 1.49, 95% CI 1.08-2.06), anti-dsDNA (HR 1.38, 95% CI 1.01-1.87), and a high number of autoantibodies (HR 1.26, 95% CI 1.06-1.48). CONCLUSION: The risk of incident proteinuria after onset of SLE was increased by the presence of lymphopenia, anti-dsDNA antibodies, psychosis, younger age, and a high number of autoantibodies at onset.

Antibodies to a strain-specific citrullinated Epstein-Barr virus peptide diagnoses rheumatoid arthritis.

Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease. Anti-citrullinated protein antibodies (ACPA) are crucial for the serological diagnosis of RA, where Epstein-Barr virus (EBV) has been suggested to be an environmental agent in triggering the onset of the disease. This study aimed to analyse antibody reactivity to citrullinated EBV nuclear antigen-2 (EBNA-2) peptides from three different EBV strains (B95-8, GD1 and AG876) using streptavidin capture enzyme-linked immunosorbent assay. One peptide, only found in a single strain (AG876), obtained a sensitivity and specificity of 77% and 95%, respectively and showed high sequence similarity to the filaggrin peptide originally used for ACPA detection. Comparison of antibody reactivity to commercial assays found that the citrullinated peptide was as effective in detecting ACPA as highly sensitive and specific commercial assays. The data presented demonstrate that the citrullinated EBNA-2 peptide indeed is recognised specifically by RA sera and that the single peptide is able to compete with assays containing multiple peptides. Furthermore, it could be hypothesized that RA may be caused by (a) specific strain(s) of EBV.