Temporal change in prevalence and complications of uveitis associated with juvenile idiopathic arthritis:data from a cross-sectional analysis of a prospective nationwide study

OBJECTIVES To analyse the nationwide prevalence of uveitis in JIA and its complications over a whole decade. METHODS We conducted a prospective, observational and cross-sectional study including all JIA patients from a National Paediatric Rheumatological Database (NPRD) with a uveitis add-on module in Germany (2002-2013). Temporal changes in uveitis prevalence, related secondary complications and anti-inflammatory medication were evaluated. RESULTS A total of 60 centres including 18,555 JIA patients (mean 3,863 patients/year, SD=837) were documented in the NPRD between 2002 and 2013. The mean age of the patients was 11.4±4.6 years, their mean disease duration 4.4±3.7 years. Among them, 66.9% were female and 51.7% ANA positive. Patients' mean age at arthritis onset was 6.9±4.5 years. Treatment rates with synthetic and biological DMARDs increased during the observation period (sDMARD: 39.8% to 47.2%, bDMARD: 3.3% to 21.8%). Uveitis prevalence decreased significantly from 2002 to 2013 (13.0% to 11.6%, OR = 0.98, p=0.015). The prevalence of secondary uveitis complications also decreased significantly between 2002 and 2013 (33.6% to 23.9%, OR=0.94, p<0.001). Among the complications, the most common ones were posterior synechiae, cataract and band keratopathy. A significant increase in achieving uveitis inactivity was observed at 30.6% in 2002 and 65.3% in 2013 (OR=1.15, p<0.001). CONCLUSIONS Uveitis prevalence and complications significantly decreased between 2002 and 2013. This may be associated with a more frequent use of DMARDs.

Impact of anti-inflammatory treatment on the onset of uveitis in juvenile idiopathic arthritis: Longitudinal analysis from a nation-wide paediatric rheumatological database

PURPOSE Based on a nation-wide database, this study analysed the influence of methotrexate (MTX), TNF inhibitors and a combination of the two on uveitis occurrence in JIA patients. METHODS Data from the National Paediatric Rheumatological Database in Germany were used in this study. Between 2002 and 2013, data from JIA patients were annually documented at the participating paediatric rheumatological sites. Patients with JIA disease duration of less than 12 months at initial documentation and ≥2 years of follow-up were included in this study. The impact of anti-inflammatory treatment on the occurrence of uveitis was evaluated by discrete-time survival analysis. RESULTS A total of 3,512 JIA patients (mean age 8.3±4.8 years, female 65.7%, ANA-positive 53.2%, mean age at arthritis onset 7.8±4.8 years) fulfilled the inclusion criteria. Mean total follow-up time was 3.6±2.4 years. Uveitis developed in a total of 180 patients (5.1%) within one year after arthritis onset. Uveitis onset after the first year was observed in another 251 patients (7.1%). DMARD treatment in the year before uveitis onset significantly reduced the risk for uveitis: MTX (HR 0.63, p=0.022), TNF inhibitors (HR 0.56, p<0.001) and a combination of the two (HR 0.10, p<0.001). Patients treated with MTX within the first year of JIA had an even a lower uveitis risk (HR 0.29, p<0.001). CONCLUSION The use of DMARDs in JIA patients significantly reduced the risk for uveitis onset. Early MTX use within the first year of disease and the combination of MTX with a TNF inhibitor had the highest protective effect. This article is protected by copyright. All rights reserved.

A Lentiviral Vector Expressing Japanese Encephalitis Virus-like Particles Elicits Broad Neutralizing Antibody Response in Pigs.

BACKGROUND Japanese encephalitis virus (JEV) is the major cause of viral encephalitis in Southeast Asia. Vaccination of domestic pigs has been suggested as a "one health" strategy to reduce viral disease transmission to humans. The efficiency of two lentiviral TRIP/JEV vectors expressing the JEV envelope prM and E glycoproteins at eliciting protective humoral response was assessed in a mouse model and piglets. METHODOLOGY/PRINCIPAL FINDINGS A gene encoding the envelope proteins prM and E from a genotype 3 JEV strain was inserted into a lentiviral TRIP vector. Two lentiviral vectors TRIP/JEV were generated, each expressing the prM signal peptide followed by the prM protein and the E glycoprotein, the latter being expressed either in its native form or lacking its two C-terminal transmembrane domains. In vitro transduction of cells with the TRIP/JEV vector expressing the native prM and E resulted in the efficient secretion of virus-like particles of Japanese encephalitis virus. Immunization of BALB/c mice with TRIP/JEV vectors resulted in the production of IgGs against Japanese encephalitis virus, and the injection of a second dose one month after the prime injection greatly boosted antibody titers. The TRIP/JEV vectors elicited neutralizing antibodies against JEV strains belonging to genotypes 1, 3, and 5. Immunization of piglets with two doses of the lentiviral vector expressing JEV virus-like particles led to high titers of anti-JEV antibodies, that had efficient neutralizing activity regardless of the JEV genotype tested. CONCLUSIONS/SIGNIFICANCE Immunization of pigs with the lentiviral vector expressing JEV virus-like particles is particularly efficient to prime antigen-specific humoral immunity and trigger neutralizing antibody responses against JEV genotypes 1, 3, and 5. The titers of neutralizing antibodies elicited by the TRIP/JEV vector are sufficient to confer protection in domestic pigs against different genotypes of JEV and this could be of a great utility in endemic regions where more than one genotype is circulating.

Reduced pro-inflammatory profile of γδT cells in pregnant patients with rheumatoid arthritis

BACKGROUND During pregnancy, many patients with rheumatoid arthritis (RA) experience disease improvement, whereas patients with ankylosing spondylitis often suffer from persistent active disease. Here we investigated whether pregnancy-related changes in disease activity were associated with changes in the proportion and function of γδT cells. METHODS The study population comprised 55 patients with RA, 31 patients with ankylosing spondylitis, and 35 healthy controls. Among these participants, 28 RA patients, 21 ankylosing spondylitis patients, and 23 healthy controls were investigated once before conception when possible, at each trimester of pregnancy, and at 8 weeks postpartum. Data were compared with age-matched non-pregnant patients to obtain disease-related background. In all subjects, peripheral Vδ1 and Vδ2 T cells were analyzed for cell frequencies, the activation marker CD69, the cytotoxicity markers NKG2D and NKG2A, and the intracellular cytokines tumor necrosis factor (TNF)α, interferon (IFN)γ, interleukin (IL)-17 and IL-10. RESULTS Pregnant patients showed a decreased Vδ2/Vδ1 ratio in the third trimester, which resulted from a slightly reduced proportion of Vδ2 cells. Changes in RA disease activity during pregnancy and postpartum were not associated with numerical proportions of γδT cells but with changes of the cell activation marker CD69 on Vδ1 and Vδ2 cells. Only RA patients showed reduced proportions of TNFα-positive Vδ1and Vδ2 cells and IFNγ-positive Vδ2 cells at the third trimester of pregnancy, a finding that was not apparent in the entire population of CD3 T cells. The proportions of IL-17-positive γδT cells and IL-10-positive γδT cells did not differ between pregnant and non-pregnant women of the different groups. CONCLUSIONS Changes of disease activity in pregnant RA patients were associated with functional changes in both γδT cell subsets. This reduced pro-inflammatory profile of γδT cells might contribute to the immunomodulation resulting in pregnancy-induced improvement of RA.

Citrullination in the periodontium-a possible link between periodontitis and rheumatoid arthritis

OBJECTIVES The aim of the present study was to assess human and bacterial peptidylarginine deiminase (PAD) activity in the gingival crevicular fluid (GCF) in the context of serum levels of antibodies against citrullinated epitopes in rheumatoid arthritis and periodontitis. MATERIALS AND METHODS Human PAD and Porphyromonas gingivalis-derived enzyme (PPAD) activities were measured in the GCF of 52 rheumatoid arthritis (RA) patients (48 with periodontitis and 4 without) and 44 non-RA controls (28 with periodontitis and 16 without). Serum antibodies against citrullinated epitopes were measured by ELISA. Bacteria being associated with periodontitis were determined by nucleic-acid-based methods. RESULTS Citrullination was present in 26 (50 %) RA patients and 23 (48 %) controls. PAD and PPAD activities were detected in 36 (69 %) and 30 (58 %) RA patients, respectively, and in 30 (68 %) and 21 (50 %) controls, respectively. PPAD activity was higher in RA and non-RA patients with periodontitis than in those without (p = 0.038; p = 0.004), and was detected in 35 of 59 P. gingivalis-positive samples, and in 16 of 37 P. gingivalis-negative samples in association with high antibody levels against that species. CONCLUSIONS PAD and PPAD activities within the periodontium are elevated in RA and non-RA patients with periodontitis. PPAD secreted by P. gingivalis residing in epithelial cells may exert its citrullinating activity in distant regions of the periodontium or even distant tissues. CLINICAL RELEVANCE In periodontitis, the citrullination of proteins/peptides by human and bacterial peptidylarginine deiminases may generate antibodies after breaching immunotolerance in susceptible individuals.

Regulation of peripheral classical and non-classical monocytes on infliximab treatment in patients with rheumatoid arthritis and ankylosing spondylitis.

OBJECTIVE To investigate the regulatory effect of tumour necrosis factor (TNF) blockade with infliximab on the distribution of peripheral blood monocyte subpopulations in patients with rheumatoid arthritis (RA) and ankylosing spondylitis (AS). METHODS Purified CD11b+CD14+ monocytes from 5 patients with RA and 5 AS were analysed ex vivo before and after infliximab treatment by flow cytometry for CD16, CD163, CD11b, C-C chemokine receptor type 2 (CCR2) and CXC chemokine receptor 4 (CXCR4) at baseline and at days 2, 14, 84 and 168 after the first infliximab administration. Serum levels of the stromal cell-derived factor (SDF)-1 and monocyte chemotactic peptide (MCP)-1 at different time points were measured in either patient group before and on infliximab treatment. RESULTS Anti-TNF treatment with infliximab led to a significant increase of circulating CD11b+ non-classical and a concomitantly decrease of CD11b+ classical monocytes, to a decline in SDF-1 levels and reduced expression of CCR2 and CXCR4 on non-classical monocyte subpopulation. CONCLUSIONS Our study shows, that TNFα blockade by infliximab resulted in a dichotomy of the regulation of classical and non-classical monocytes that might have substantial impact on inhibition of osteoclastogenesis and of subsequent juxta-articular bone destruction and systemic bone loss in RA and AS.

Prevalence estimation of tick-borne encephalitis virus (TBEV) antibodies in dogs from Finland using novel dog anti-TBEV IgG MAb-capture and IgG immunofluorescence assay based on recombinant TBEV subviral particles

Tick-borne encephalitis (TBE) is one of the most dangerous human neurological infections occurring in Europe and Northern parts of Asia with thousands of cases and millions vaccinated against it. The risk of TBE might be assessed through analyses of the samples taken from wildlife or from animals which are in close contact with humans. Dogs have been shown to be a good sentinel species for these studies. Serological assays for diagnosis of TBE in dogs are mainly based on purified and inactivated TBEV antigens. Here we describe novel dog anti-TBEV IgG monoclonal antibody (MAb)-capture assay which is based on TBEV prME subviral particles expressed in mammalian cells from Semliki Forest virus (SFV) replicon as well as IgG immunofluorescence assay (IFA) which is based on Vero E6 cells transfected with the same SFV replicon. We further demonstrate their use in a small-scale TBEV seroprevalence study of dogs representing different regions of Finland. Altogether, 148 dog serum samples were tested by novel assays and results were compared to those obtained with a commercial IgG enzyme immunoassay (EIA), hemagglutination inhibition test and IgG IFA with TBEV infected cells. Compared to reference tests, the sensitivities of the developed assays were 90-100% and the specificities of the two assays were 100%. Analysis of the dog serum samples showed a seroprevalence of 40% on Åland Islands and 6% on Southwestern archipelago of Finland. In conclusion, a specific and sensitive EIA and IFA for the detection of IgG antibodies in canine sera were developed. Based on these assays the seroprevalence of IgG antibodies in dogs from different regions of Finland was assessed and was shown to parallel the known human disease burden as the Southwestern archipelago and Åland Islands in particular had considerable dog TBEV antibody prevalence and represent areas with high risk of TBE for humans.

Genomic amplification of the caprine EDNRA locus might lead to a dose dependent loss of pigmentation

The South African Boer goat displays a characteristic white spotting phenotype, in which the pigment is limited to the head. Exploiting the existing phenotype variation within the breed, we mapped the locus causing this white spotting phenotype to chromosome 17 by genome wide association. Subsequent whole genome sequencing identified a 1 Mb copy number variant (CNV) harboring 5 genes including EDNRA. The analysis of 358 Boer goats revealed 3 alleles with one, two, and three copies of this CNV. The copy number is correlated with the degree of white spotting in goats. We propose a hypothesis that ectopic overexpression of a mutant EDNRA scavenges EDN3 required for EDNRB signaling and normal melanocyte development and thus likely lead to an absence of melanocytes in the non-pigmented body areas of Boer goats. Our findings demonstrate the value of domestic animals as reservoir of unique mutants and for identifying a precisely defined functional CNV.