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Rheumatoid arthritis (RA) and periodontitis are chronic inflammatory diseases with several pathogenic pathways in common. Evidence supports an association between the diseases, but the exact underlying mechanisms behind the connection are still under investigation. Lipid, fatty acid (FA) and metabolic profile alterations have been associated with several chronic inflammatory diseases, including RA and periodontitis. Mitochondria have a central role in regulating cellular bioenergetic and whole-body metabolic homeostasis, and mitochondrial dysfunction has been proposed as a possible link between the two disorders. The aim of this cross-sectional study was to explore whole-blood FA, serum lipid composition, and carnitine- and choline derivatives in 78 RA outpatients with different degrees of periodontal inflammation. The main findings were alterations in lipid, FA, and carnitine- and choline derivative profiles. More specifically, higher total FA and total cholesterol concentrations were found in active RA. Elevated phospholipid concentrations with concomitant lower choline, elevated medium-chain acylcarnitines (MC-AC), and decreased ratios of MC-AC and long-chain (LC)-AC were associated with prednisolone medication. This may indicate an altered mitochondrial function in relation to the increased inflammatory status in RA disease. Our findings may support the need for interdisciplinary collaboration within the field of medicine and dentistry in patient stratification to improve personalized treatment. Longitudinal studies should be conducted to further assess the potential impact of mitochondrial dysfunction on RA and periodontitis.

International audience; Objective. Juvenile Sjögren's syndrome (SS) is a rare, poorly defined, and possibly underdiagnosed condition affecting children and adolescents. The aim of this study was to characterize symptoms and clinical findings of juvenile SS and to explore the clinical application of major salivary gland ultrasonography (SGUS) in patients with juvenile SS. Methods. A cross-sectional multicenter study recruited patients with disease onset until age 18 years (n = 67). Disease characteristics were recorded, and unstimulated whole sialometry and SGUS examination of the parotid and submandibular salivary glands were performed. Results. The female:male ratio was 58:9. The mean age at first symptom was 10.2 years and 12.1 years at diagnosis. Ocular and oral symptoms were noted in 42 of 67 patients (63%) and 53 of 66 patients (80%), respectively. The American-European Consensus Group or American College of Rheumatology/European League Against Rheumatism classification criteria for primary SS were fulfilled by 42 of 67 patients (63%). Pathologic SGUS findings were observed in 41 of 67 patients (61%); 26 of 41 SGUS+ patients (63%) fulfilled primary SS criteria. Salivary gland enlargements/parotitis were noted in 37 of 58 patients and were nonsignificantly associated with SGUS+ status (P = 0.066). The mean levels of saliva were 5.6 ml/15 minutes in SGUS-patients compared to 3.3 ml/15 minutes in the SGUS+ patients (P = 0.049). A total of 36 of 41 SGUS+ patients (88%) were anti-Ro/La+ compared to 14 of 26 SGUS-patients (54%) (P = 0.001). In addition, 24 of 39 SGUS+ patients (62%) were positive for rheumatoid factor (RF), whereas only 5 of 25 SGUS-patients (20%) were RF+ (P = 0.001). Conclusion. Juvenile SS is characterized by a large spectrum of clinical symptoms and findings. Several glandular and extraglandular parameters such as hyposalivation, swollen salivary glands, and autoantibodies are associated with pathologic SGUS findings.

Sjögren's disease is a complex autoimmune disease with twelve established susceptibility loci. This genome-wide association study (GWAS) identifies ten novel genome-wide significant (GWS) regions in Sjögren's cases of European ancestry: CD247, NAB1, PTTG1-MIR146A, PRDM1-ATG5, TNFAIP3, XKR6, MAPT-CRHR1, RPTOR-CHMP6-BAIAP6, TYK2, SYNGR1. Polygenic risk scores yield predictability (AUROC = 0.71) and relative risk of 12.08. Interrogation of bioinformatics databases refine the associations, define local regulatory networks of GWS SNPs from the 95% credible set, and expand the implicated gene list to40. Many GWS SNPs are eQTLs for genes within topologically associated domains in immune cells and/or eQTLs in the main target tissue, salivary glands.

There is a critical need to deconvolute the heterogeneity displayed by the minor salivary glands of primary Sjögren’s syndrome (pSS) patients. This is challenging primarily because the disease etiology remains unknown. The hypothesis includes that initial events in the disease pathogenesis target the salivary glands, thereby triggering the development of focal infiltrates (≥50 mononuclear cells) and finally germinal center-like structures. However, the proportion of key mononuclear immune cells residing at these sites, in combination with the overall ratio of morphometric tissue atrophy and adipose infiltration within the minor salivary glands (MSG) parenchyma at distinct phases of inflammatory disease establishment and progression have not been quantified in detail. In this cross-sectional study, we intended to address this problem by stratifying 85 patients into mild (S1), moderate (S2), and severe (S3) stages using the Inflammatory severity index. We found that mild (p <0.01), but not in pSS patients. The percentage of adipose infiltration significantly correlated with the age of patients (r = 0.458, p <0.0001) and controls (r = 0.515, p <0.0001). The CD4+ T helper cell incidence was reduced in the focal infiltrates of the MSG of S2 patients compared to S1 (p <0.01), and in S2 compared to S1 and S3 combined (p <0.05). CD20+ B cells increased from S1 to S3 (p <0.01) and S2 to S3 (p <0.01), meanwhile CD138+ plasma cells diminished in S3 patients compared to both S1 and S2 groups combined (p <0.01). The proportion of patients with anti-Ro/SSA+, anti-La/SSB+, and RF+ increased over the course of inflammatory disease progression and they were significantly more common in the S3 group relative to S1 (p <0.05). On the other hand, S2 patients measured a higher mean salivary flow relative to S1 and S3 patients combined (p <0.05). Our results demonstrate how the proposed Inflammatory severity index stratification revealed pathological cell and tissue-associated aberrations in the salivary component over the course of inflammatory progression, and their correlations to clinical outcomes. This could be directly transferred to the optimization of available diagnostic strategies applied for pSS patients.

Assess if kynurenines metabolites are biomarkers of damage at labial salivary gland biopsy (LSGB).This is a cross-sectional study including 99 patients with primary Sjögren's syndrome (AECG 2002 or ACR/EULAR 2017). Kynurenines were measured in plasma using liquid chromatography-tandem mass spectrometry.95.9% were females, 51±12 years. Most had focal lymphocytic sialadenitis with focus score ≥1 (73.7%, n=73/99). The majority had mild to severe acinar atrophy (70.4%, n=57/81) and adipose infiltration (51.2%, n=39/80). Individuals with adipose infiltration were older (53.49±12.33 vs. 47.51±11.29 years, p=0.016), showed higher frequency of glandular dysfunction and higher kynurenines levels. Schirmer's test ≤ 5 mm/5min was found in 69.2% of individuals with adipose infiltration compared to 41% without (p=0.012) and unstimulated whole salivary flow (UWSF) was found in 87.2% compared to 70% without adipose infiltration (p=0.063). Additionally, individuals with adipose infiltration showed higher kynurenines metabolites compared with those without: quinolinic acid (503.35±193.30 vs. 427.35±285.76 nmol/L, p=0.029), kynurenine (1.99±0.6, 54 vs. 1.61±0.46 μmol/L, p=0.006), kynurenine/tryptophan ratio (KTR) (0.030±0.09 vs. 0.025±0.01, p=0.031) and anthranilic acid (03±4.96 vs. 16.46±5.24 nmol/L, p=0.022).Kynurenines are biomarkers of greater adipose infiltration in LSGB and glandular dysfunction suggesting that activation of interferon-γ pathway is involved in the salivary and lacrimal glands damage.

Background To better understand and evaluate clinical usefulness of magnetic resonance imaging (MRI) in diagnosis and treatment of temporomandibular disorders (TMD), parameters for the evaluation are useful. Purpose To assess a clinically suitable staging system for evaluation of MRI of the temporomandibular joint (TMJ) and correlate the findings with age and some clinical symptoms of the TMJ. Material and Methods Retrospective analysis of 79 consecutive patients with clinical temporomandibular disorder or diagnosed inflammatory arthritis. Twenty-six healthy volunteers were included as controls. Existing data included TMJ pain, limited mouth opening (Results The patients with clinical TMD complaints had statistically significantly more anterior disc displacement (ADD), disc deformation, caput flattening, surface destructions, osteophytes, and caput edema diagnosed by MRI compared to the controls. Among the arthritis patients, ADD, effusion, caput flattening, surface destructions, osteophytes, and caput edema were significantly more prevalent compared to the healthy volunteers. In the control group, disc deformation and presence of osteophytes significantly increased with age, and a borderline significance was found for ADD and surface destructions on the condylar head. No statistically significant associations were found between investigated clinical and MRI parameters. Conclusion This study presents a clinically suitable staging system for comparable MRI findings in the TMJs. Our results indicate that some findings are due to age-related degenerative changes rather than pathological changes. Results also show that clinical findings such as pain and limited mouth opening may not be related to changes diagnosed by MRI.

Primary Sjögren's syndrome (pSS) is a complex systemic autoimmune disease with heterogeneous disease manifestations. Genetic predisposition, hormonal and environmental factors are all thought to contribute to disease etiology and pathogenesis. A better understanding of the disease pathogenesis is required in order to establish new targeted therapies. We analysed MAPK/ERK and JAK/STAT signalling networks in peripheral blood mononuclear cells (PBMCs) upon stimulation with interferon alpha 2b (IFN‐α2b) by flow cytometry to define potentially dysfunctional intracellular signalling pathways involved in disease pathogenesis. Cells derived from pSS patients displayed small but significant increases in basal phosphorylation levels of numerous signalling proteins compared to cells from healthy donors. The phosphorylation profiles following stimulation with IFNα2b differed significantly between pSS patients and healthy donors, especially regarding STAT1 Y701. PCA further grouped patients according to clinical characteristics. Type I IFN induced gene expression was found to negatively correlate with the IFN‐α2b induced phosphorylation of STAT3 S727 in T cells and positively with pSTAT1 Y701 in B cells. Increases in pSTAT1 Y701 were associated with the presence of autoantibodies. Our results indicate involvement of both STAT3 S727 and STAT1 Y701 pathways in pSS patients. Therapies targeting these pathways might therefore be beneficial for certain subgroups of patients.

Background: Despite men being less prone to develop autoimmune diseases, male sex has been associated with a more severe disease course in several systemic autoimmune diseases. In the present study, we aimed to investigate differences in the clinical presentation of primary Sjogrens syndrome (pSS) between the sexes and establish whether male sex is associated with a more severe form of long-term pSS. Methods: Our study population included 967 patients with pSS (899 females and 68 males) from Scandinavian clinical centers. The mean follow-up time (years) was 8.8 +/- 7.6 for women and 8.5 +/- 6.2 for men (ns). Clinical data including serological and hematological parameters and glandular and extraglandular manifestations were compared between men and women. Results: Male patient serology was characterized by more frequent positivity for anti-Ro/SSA and anti-La/SSB (p = 0. 02), and ANA (p = 0.02). Further, men with pSS were more frequently diagnosed with interstitial lung disease (p = 0. 008), lymphadenopathy (p = 0.04) and lymphoma (p = 0.007). Conversely, concomitant hypothyroidism was more common among female patients (p = 0.009). Conclusions: We observe enhanced serological responses and higher frequencies of lymphoma-related extraglandular manifestations in men with pSS. Notably, lymphoma itself was also significantly more common in men. These observations may reflect an aggravated immune activation and a more severe pathophysiological state in male patients with pSS and indicate a personalized managing of the disease due to the influence of the sex of patients with pSS. Funding Agencies|Swedish Research Council; Heart-Lung Foundation; Stockholm County Council; Karolinska Institutet; Swedish Rheumatism association; King Gustaf the Vth 80-year foundation; AstraZeneca Science for Life Laboratory Research Collaboration grant

Objective Rheumatoid arthritis (RA) and periodontitis are chronic inflammatory diseases that share common risk factors. However, the bidirectional relationship between RA and periodontal disease is not fully understood. This study was undertaken to describe the bacterial component of the subgingival microbiome in RA patients and to relate this to RA disease activity and periodontal status. Methods Patients with chronic established RA (N = 78) were periodontally examined and their subgingival plaque samples were collected; their clinical and laboratory data on RA status and medication were obtained from medical records. Bacterial DNA was quantified by universal 16S rDNA qPCR, and Porphyromonas gingivalis by species-specific qPCR. For microbiome assessment, 16S rDNA amplicon sequencing was performed. Results Active RA was diagnosed in 58% of the patients and periodontitis in 82% (mild: 9%, moderate: 55%, severe: 18%). P. gingivalis was present in 14% of the samples. Different levels of gingival bleeding, periodontal probing depth, RA disease status, prednisolone use and smoking were associated with significantly different microbiome compositions. Two subgingival microbial community types were discerned. Conclusion In RA patients with active disease, anti-inflammatory medication as part of RA therapy was associated with better oral health status and a healthier subgingival microbiome compared to that of RA patients in remission, especially those in remission who were current smokers. RA patients in remission with current smoking status may particularly benefit from a systematic periodontal treatment program. The potential role of microbial community types in patient stratification and personalized therapy should be assessed in longitudinal studies.

OBJECTIVES: Marine ω-3 fatty acids (FAs) and Vitamin D (VitD) are reportedly capable of down-regulating inflammation in rheumatoid arthritis (RA) and periodontal disease. This study was undertaken to relate marine FA and VitD status to RA disease status and periodontal conditions.METHODS: RA outpatients (age ≥35 y) were consecutively recruited. Rheumatologic clinical data were collected and periodontal status obtained. A food frequency questionnaire was used to estimate fish and supplement intake. FA profiles in whole-blood and serum VitD levels were determined.RESULTS: A total of 78 RA patients (age 57 ± 12 y, disease duration 15 ± 11 y) were included, 58% had active RA. Periodontitis was diagnosed in 82% of the patients, 18% had severe periodontitis. Seropositivity for rheumatoid factor and/or anticitrullinated protein antibodies was related to higher prevalence of periodontitis (P= 0.008). Seafood intake in accordance with nutritional recommendations was associated with better RA disease outcome (largest P= 0.008). An ω-3 index >8, present in 14% of the patients, correlated with a more desirable patient global health assessment scored on a visual analog scale (VAS; P= 0.004), lower periodontal probing depth (PD; P= 0.021), and ω-3 supplementation (P= 0.001). Serum VitD levels >50 nmol/L were found in 89%, of these 48% had VitD levels ≥75 nmol/L, no differences were found for RA disease activity and periodontal measurements.CONCLUSIONS: Seropositive RA patients had a higher prevalence of periodontitis than seronegative patients. An ω-3 index >8 was related to ω-3 supplementation and more desirable VAS and lower PD. VitD status was satisfactory for most patients and was not associated with differences in RA severity or periodontal diagnosis.

Primary Sjögren's syndrome (pSS) is a chronic, inflammatory autoimmune disease characterised by lymphocytic infiltrations in the exocrine glands, resulting in destruction of salivary and lacrimal glands. B cells have an important role in the disease, as detection of autoantibodies against SSA/Ro or SSB/La is one of the diagnostic criteria, being found in a majority of the patients. Toll-like receptors (TLR) are pattern recognition receptors. TLR-7 and -9 are found in endosomes and bind microbial nucleic acids. We have previously shown that pSS patients and healthy controls have similar expression pattern of TLR-7 and -9 in various B-cell populations. In this study we further analysed the responsiveness of B cells upon TLR stimulation. B cells isolated from peripheral blood of 21 pSS patients and 18 healthy controls were stimulated with TLR-7 and -9 ligands for 24 h before being analysed for the expression of certain surface markers and intracellular cytokine levels by flow cytometry. Secreted cytokines were measured by a multiplex cytokine assay. Patients with pSS had more naïve and less preswitched memory B cells compared to controls in unstimulated as well as via TLR-7 stimulated cells. Unstimulated and via TLR-7 stimulated B cells from pSS patients also had fewer IL-10(+) preswitched memory B cells. Moreover, TLR-7 and -9 stimulated B cells of pSS patients secreted increased amounts of several cytokines. B cells of pSS patients show a different responsiveness upon stimulation of TLR-7 and -9 compared to controls.

Objective Dependence on invasive procedures for classification of patients with Sjogren's syndrome (SS) hampers timely diagnosis and suitable patient followup. The aim of this study was to recapitulate the diagnosis of SS through noninvasive means and to define the biologic state of SS patients' salivary glands. Methods Using a 187-plex capture antibody–based assay, salivary proteomic biomarker profiles were generated from patients with primary SS, patients with rheumatoid arthritis, and asymptomatic controls. Discriminant function analyses and Gene Ontology–based network analyses allowed data analyses with a reductionist approach and with a focus on systems biology. Results Characterized by significant changes in 61 and 55 proteins, respectively, the salivary proteome of SS patients appeared profoundly altered compared to that of individuals without SS. On this basis, 4-plex and 6-plex biomarker signatures, both including interleukin-4 (IL-4), IL-5, and clusterin, achieved accurate prediction of an individual's group membership for at least 94% of cases. Of note, all misclassified SS patients presented with ectopic germinal center–like structures. Systematic inference of biologic meaning identified SS-related protein patterns delineating B cell–dominated immune responses, macrophage differentiation, and signs of T cell chemotaxis. In addition, proteomic Multi-Analyte Profiles provided insight about proteins related to collagen, cytokine, and growth factor synthesis as well as lipid transport. Conclusion The SS-related molecular landscape conveyed by saliva showed great congruence with histopathologic features found in SS and advances understanding of this disease at a molecular level. Such salivary biomarker signatures harbor great potential for improving timeliness of SS diagnosis and enabling suitable patient followup.

Background Juvenile Sjogren9s syndrome (jSS) is a rare, poorly defined and possibly underdiagnosed condition. There is little information on the use of major salivary gland ultrasonography (SGUS) in this patient-group. Objectives To characterize symptoms and clinical findings of jSS and to investigate SGUS as a diagnostic tool. Methods Sixty-four patients were recruited from Brazil (n=40), Norway (n=11), the Netherlands (n=8) and Spain (n=5). All patients had disease onset at the age of 18 or younger. Clinical examination and sialometry was performed in 60/64 patients. Additional clinical information was obtained from the medical records and through patient interview. SGUS of the parotid and submandibular glands was performed in all patients using linear high-frequency transducers (6–15 MHz), by an expert in SGUS. Glandular homogeneity and presence of hypoechogenic areas were evaluated and glands characterized as normal or SS-like. Results The female:male ratio was 6:1. Mean age at diagnosis was 12.1 years (range 4–18), with first symptoms occurring at 10.3 years (range 1–17). Time from onset of symptoms until diagnosis was 1.6 years (range -2–8 years). Subjective oral and ocular symptoms were reported in 70% and 64% patients, respectively. Reduced secretion of tears was detected in 41% patients, and hyposalivation in 31% patients. Minor salivary gland lip biopsy had been performed and focus score determined in 34 patients; 28 biopsies (82%) had focus score ≥1. Serologically, 92% were positive for ANA, 73% were anti-Ro/SSA+, 38% were anti-La/SSB+, and 41% were RF+. Salivary gland enlargement had been experienced by 53% of the patients; one patient had also experienced lacrimal gland enlargement. Systemic manifestations at some time-point, was registered in 66% of the patients. Systemic treatment at inclusion was registered in 67% of the patients; previous systemic treatment was registered in 83%. Diagnostic criteria for primary Sjogren9s syndrome (pSS) was fulfilled by 34/64 patients (53%) and 39/64 patients (61%), AECG criteria and ACR/EULAR criteria, respectively. SGUS revealed SS-like changes in 37/64 patients (59%); interestingly, SS-like findings were observed in 22/23 patients in the European cohort, compared to 15/40 patients in the Brazilian cohort. Conclusions Common symptoms and findings in jSS include dry mouth, systemic manifestations and salivary gland enlargement, followed by reduced tear secretion and hyposalivation. Disclosure of Interest None declared

An accurate dissection of peripheral blood enumeration is lacking in primary Sjogren's syndrome (pSS). The purpose of this study was to quantify different leucocyte populations in peripheral blood of patients with pSS. Numbers of specific leucocyte subsets were determined in 86 pSS patients and 74 healthy donors quantifying 21 distinct subtypes by flow cytometry. Subgroups of pSS patients were stratified based on presence of extraglandular manifestations (EGMs) and SSA/SSB autoantibodies. Overall, pSS patients manifested decreased lymphocyte subpopulations compared to healthy donors. Such decreases were more pronounced in SSA/SSB positive patients and patients with EGM. Granulocyte and monocyte subpopulations were increased in pSS patients compared to healthy donors, with the greatest increases in SSA/SSB positive patients. Unsupervised hierarchal clustering based on cell quantities was used to further subgroup the pSS patients into four clusters. One of the clusters characterized by higher concentrations of NKT cells, CD56hi NK cells, CD20+ CD38- B cells and CD8+ CD38- T cells was associated with weaker clinical symptoms than the other clusters, possibly marking a milder disease phenotype. In conclusion, our analyses indicate significant alterations in the cellular profiles of peripheral blood leucocytes in patients with pSS and may help to stratify the patients according to disease severity.

Sjögren’s syndrome (SS) is a common, autoimmune exocrinopathy distinguished by keratoconjunctivitis sicca and xerostomia. Patients frequently develop serious complications including lymphoma, pulmonary dysfunction, neuropathy, vasculitis, and debilitating fatigue. Dysregulation of type I interferon (IFN) pathway is a prominent feature of SS and is correlated with increased autoantibody titers and disease severity. To identify genetic determinants of IFN pathway dysregulation in SS, we performed cis-expression quantitative trait locus (eQTL) analyses focusing on differentially expressed type I IFN-inducible transcripts identified through a transcriptome profiling study. Multiple cis-eQTLs were associated with transcript levels of 2'-5'-oligoadenylate synthetase 1 (OAS1) peaking at rs10774671 (PeQTL = 6.05 × 10−14). Association of rs10774671 with SS susceptibility was identified and confirmed through meta-analysis of two independent cohorts (Pmeta = 2.59 × 10−9; odds ratio = 0.75; 95% confidence interval = 0.66–0.86). The risk allele of rs10774671 shifts splicing of OAS1 from production of the p46 isoform to multiple alternative transcripts, including p42, p48, and p44. We found that the isoforms were differentially expressed within each genotype in controls and patients with and without autoantibodies. Furthermore, our results showed that the three alternatively spliced isoforms lacked translational response to type I IFN stimulation. The p48 and p44 isoforms also had impaired protein expression governed by the 3' end of the transcripts. The SS risk allele of rs10774671 has been shown by others to be associated with reduced OAS1 enzymatic activity and ability to clear viral infections, as well as reduced responsiveness to IFN treatment. Our results establish OAS1 as a risk locus for SS and support a potential role for defective viral clearance due to altered IFN response as a genetic pathophysiological basis of this complex autoimmune disease., Author summary Sjögren’s syndrome (SS) is a common autoimmune condition where immune cells infiltrate moisture-producing glands, leading to dryness typically in the eyes and mouth. SS patients also manifest debilitating fatigue as well as other diseases in liver, lung, kidney, and skin. The cause of this complex disease is still not fully understood; however, an environmental trigger, such as viral infections, in individuals with genetic risk factor(s) is thought to contribute to the development of SS. Type 1 interferons (IFNs) are one of the first defenders after viral infection and induce the expression of various virus-responding genes. Perpetual elevation of type 1 IFN signaling has been observed in SS patients. Here, we first replicated previously identified RNA transcripts contributing to the abnormal type 1 IFN signaling in SS patients. We then identified a disease-associated genetic variant in an IFN-inducible gene, OAS1. This variant governs splicing of OAS1, altering the transcript into multiple isoforms that lack protein expression and responsiveness to IFNs. The results of this study may provide insight into the genetic basis of SS, as well as other autoimmune disease with similar dysregulation in the type 1 IFN system.

Objective: Our aim was to compare the subgingival microbiome composition in samples collected by curettes and paperpoints. Methods: Subgingival plaque of rheumatoid arthritis patients with periodontitis (N=66) or gingivitis (N=15) was collected at two timepoints by sterile curettes and paperpoints. Unused sterile paperpoints were included as controls. The microbial DNA was processed for 16S rRNA gene amplicon sequencing. The data was processed and clustered into Operational Taxonomic Units (OTUs) and assessed by multivariate analyses. Results: Unused paperpoints showed various levels of DNA contamination. The OTUs specific for unused paperpoints were classified as Exiguobacterium, Enterococcus, Methylobacterium, Aquabacterium and Pseudomonas and were removed from the dataset. Microbial profiles of curette samples differed significantly from the paperpoint samples (PERMANOVA, p=0.0009, F=3.167). The paperpoint samples had significantly higher proportion of OTUs classified as Streptococcus, Gemella, Parvimonas, Haemophilus, Aggregatibacter and Clostridiales family XIII incertae sedis (p

ObjectivesTo analyse the influence of geolocation and ethnicity on the clinical presentation of primary Sjögren's syndrome (SjS) at diagnosis.MethodsThe Big Data Sjögren Project Consortium is an international, multicentre registry designed in 2014. By January 2016, 20 centres from five continents were participating. Multivariable logistic regression analyses were performed.ResultsWe included 7748 women (93%) and 562 men (7%), with a mean age at diagnosis of primary SjS of 53 years. Ethnicity data were available for 7884 patients (95%): 6174 patients (78%) were white, 1066 patients (14%) were Asian, 393 patients (5%) were Hispanic, 104 patients (1%) were black/African-American and 147 patients (2%) were of other ethnicities. SjS was diagnosed a mean of 7 years earlier in black/African-American compared with white patients; the female-to-male ratio was highest in Asian patients (27:1) and lowest in black/African-American patients (7:1); the prevalence of sicca symptoms was lowest in Asian patients; a higher frequency of positive salivary biopsy was found in Hispanic and white patients. A north-south gradient was found with respect to a lower frequency of ocular involvement in northern countries for dry eyes and abnormal ocular tests in Europe (OR 0.46 and 0.44, respectively) and Asia (OR 0.18 and 0.49, respectively) compared with southern countries. Higher frequencies of antinuclear antibodies (ANAs) were reported in northern countries in America (OR=1.48) and Asia (OR=3.80) while, in Europe, northern countries had lowest frequencies of ANAs (OR=0.67) and Ro/La (OR=0.69).ConclusionsThis study provides the first evidence of a strong influence of geolocation and ethnicity on the phenotype of primary SjS at diagnosis.

Exploiting genotyping, DNA sequencing, imputation and trans-ancestral mapping, we used Bayesian and frequentist approaches to model the IRF5-TNPO3 locus association, now implicated in two immunotherapies and seven autoimmune diseases. Specifically, in systemic lupus erythematosus (SLE), we resolved separate associations in the IRF5 promoter (all ancestries) and with an extended European haplotype. We captured 3230 IRF5-TNPO3 high-quality, common variants across 5 ethnicities in 8395 SLE cases and 7367 controls. The genetic effect from the IRF5 promoter can be explained by any one of four variants in 5.7 kb (P-valuemeta = 6 × 10-49; OR = 1.38-1.97). The second genetic effect spanned an 85.5-kb, 24-variant haplotype that included the genes IRF5 and TNPO3(P-valuesEU = 10-27-10-32, OR = 1.7-1.81). Many variants at the IRF5 locus with previously assigned biological function are not members of either final credibleset of potential causal variants identified herein. In addition to the known biologically functional variants, we demonstrated that the risk allele of rs4728142, a variant in the promoter among the lowest frequentist probability and highest Bayesian posterior probability, was correlated with IRF5 expression and differentially binds the transcription factor ZBTB3. Our analytical strategy provides a novel framework for future studies aimed at dissecting etiological genetic effects. Finally, both SLE elements of the statistical model appear to operate in Sjögren's syndrome and systemic sclerosis whereas only the IRF5-TNPO3 gene-spanning haplotype is associated with primary biliary cirrhosis, demonstrating the nuance of similarity and difference in autoimmune disease risk mechanisms at IRF5-TNPO3. © The Author 2014.

Primary Sjögren's syndrome (SS) is a systemic autoimmune inflammatory disease characterized by focal lymphocytic infiltrates in the lachrymal and salivary glands and autoantibodies against the SSA/Ro and SSB/La antigens. Experimental studies have shown an activation of NF-κB in primary SS. NF-κB activation results in inflammation and autoimmunity and is regulated by inhibitory and activating proteins. Genetic studies have shown an association between multiple autoimmune diseases and TNFAIP3 (A20) and TNIP1 (ABIN1), both repressors of NF-κB and of IKBKE (IKKε), which is an NF-κB activator. The aim of this study was to analyse single nucleotide polymorphisms (SNPs) in the IKBKE, NFKB1, TNIP1 and TNFAIP3 genes for association with primary SS. A total of 12 SNPs were genotyped in 1105 patients from Scandinavia (Sweden and Norway, n = 684) and the UK (n = 421) and 4460 controls (Scandinavia, n = 1662, UK, n = 2798). When patients were stratified for the presence of anti-SSA and/or anti-SSB antibodies (n = 868), case-control meta-analysis found an association between antibody-positive primary SS and two SNPs in TNIP1 (P = 3.4 × 10(-5) , OR = 1.33, 95%CI: 1.16-1.52 for rs3792783 and P = 1.3 × 10(-3) , OR = 1.21, 95%CI: 1.08-1.36 for rs7708392). A TNIP1 risk haplotype was associated with antibody-positive primary SS (P = 5.7 × 10(-3) , OR = 1.47, 95%CI: 1.12-1.92). There were no significant associations with IKBKE, NFKB1 or TNFAIP3 in the meta-analysis of the Scandinavian and UK cohorts. We conclude that polymorphisms in TNIP1 are associated with antibody-positive primary SS.

Fatigue is prevalent and disabling in primary Sjogren’s syndrome (pSS). Results from studies in chronic fatigue syndrome (CFS) indicate that genetic variation may influence fatigue. The aim of this study was to investigate single nucleotide polymorphism (SNP) variations in pSS patients with high and low fatigue. A panel of 85 SNPs in 12 genes was selected based on previous studies in CFS. A total of 207 pSS patients and 376 healthy controls were genotyped. One-hundred and ninety-three patients and 70 SNPs in 11 genes were available for analysis after quality control. Patients were dichotomized based on fatigue visual analogue scale (VAS) scores, with VAS

Objective Primary Sjogren's syndrome (SS) is associated with an increased risk of non-Hodgkin's lymphoma (NHL), but the reported prevalence and risk vary considerably. The objective of this study was to determine the risk of NHL in a well-defined population-based primary SS cohort in Norway. Methods The authors examined all patients fulfilling the American–European Consensus Group criteria for primary SS from 2 Norwegian counties and compared the data to the Cancer Registry of Norway to identify the primary SS patients who had lymphoma. In addition, lymphoma patient files from the same period were reviewed for undiagnosed primary SS to ensure the quality of registry data. Results As of July 1, 2009, 443 living subjects with primary SS were identified in an area with 896,840 inhabitants, which is 18.6% of the total population of Norway. Seven cases of NHL (1.6%) were found during a total followup of 3,813 person-years, resulting in a standardized incidence ratio of 9.0 (95% confidence interval 7.1–26.3) for NHL in primary SS patients. Conclusion The risk of NHL in patients with primary SS in Norway is increased 9 times compared with the general population. This is in accordance with recent studies, and the quality and completeness of the registries and strict use of diagnostic criteria support the validity of the results.

The pro-inflammatory proteins calprotectin (a heterocomplex of S100A8/A9) and S100A12 have been associated with disease activity in rheumatoid arthritis (RA). The aim of this study was to compare their potential as biomarkers in a prospective study of RA patients starting with infliximab as their first biological disease-modifying anti-rheumatic drug (DMARD).Thirty-nine RA patients were examined and serum samples collected when starting with infliximab and after 3, 6, and 12 months. Calprotectin and S100A12 were analysed by enzyme-linked immunosorbent assays (ELISAs) and, together with C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR), measured at all time points. A disease activity score of 28 joints (DAS28) was calculated. Radiographs of the hands, wrists, and feet were taken at baseline and after 3 years, and assessed according to the modified Sharp/van der Heijde (SvH) score. Responsiveness was evaluated according to the European League of Associations for Rheumatology (EULAR) response criteria based on 28 joints.Both S100 proteins were significantly higher in seropositive than in seronegative patients (p = 0.01). Calprotectin correlated significantly with CRP (ρ = 0.51-0.75), ESR (ρ = 0.32-0.52), and DAS28 (ρ = 0.32-0.62). S100A12 correlated with calprotectin (ρ = 0.62-0.77) and CRP (ρ = 0.32-0.63). The S100 proteins, and especially calprotectin (ρ = 0.23-0.39), showed weak associations with radiographic progression, unlike CRP/ESR. None of the S100 proteins could predict responsiveness.Calprotectin showed the strongest correlation with measures of disease activity and may be better than S100A12 when evaluating disease activity in RA patients. More extensive studies are needed to further compare the predictive value of the S100 proteins relative to radiographic progression.

Objective Clinical expression of SS shows considerable interpatient heterogeneity. Thus, the aim of this study was to assess whether individual salivary proteomic profiles provide a framework for identification of disease-phenotype-driven biomarker signatures. Methods Using a 187-plex capture antibody-based assay, proteomic biomarker profiles from unstimulated whole saliva were generated from a SS-cohort representing six clinically distinct disease phenotypes. Discriminant function analyses identified the most powerful biomarker signatures for correct recapitulation of each patient's status with respect to hyposalivation and histopathological features of salivary gland inflammation. In addition, gene ontology-based network analyses allowed systematic interpretation of the molecular patterns underlying these specific disease features. Results Presentation of hyposalivation was associated with significant alteration in 22 out of 119 reliably detectable biomarkers. Thereof, a 4-plex signature allowed accurate prediction of salivary gland function for >80% of the cases. With respect to histopathological features, the most distinct profiles were identified in conjunction with ectopic germinal centres. Selected from the 13 analytes relevant here, pregnancy-associated plasma protein A, thrombospondin 1 and peptide YY would recapitulate the presence or absence of tertiary lymphoid organization for 93.8% of the patients. Whereas functional annotation of alterations associated with hyposalivation identified the IL1 system as a dominant pro-inflammatory component, changes observed in context with ectopic lymphoid organization revealed specific shifts in chemotactic profiles and altered regulation of apoptotic processes. Conclusion Multivariate analyses of a patient's salivary proteome could reliably recapitulate specific aspects of SS disease. Accessible and repetitively collectable, such biomarker signatures harbour great potential for patient subclassification and subsequent follow-up.

Objective.To study the efficacy of anakinra versus disease-modifying antirheumatic drugs (DMARD) in refractory adult-onset Still’s disease (AOSD).Methods.In a 24-week study, 22 patients with AOSD taking prednisolone ≥ 10 mg/day received anakinra (n = 12) or DMARD (n = 10). The primary endpoint was achievement of remission.Results.At 8 and 24 weeks, 7/12 and 6/12 receiving anakinra and 5/10 and 2/10 receiving DMARD achieved remission. Anakinra induced greater improvement in physical health measured by Medical Outcomes Study Short-Form 36 (SF-36; p < 0.011). During an open-label extension (OLE) of 28 weeks, 7/14 patients taking anakinra and 2/3 taking DMARD were in remission.Conclusion.Anakinra induced more beneficial responses than DMARD in patients with AOSD and was favored in the OLE phase. (ClinicalTrials.gov Protocol Registration NCT01033656).

Sjogren's syndrome (SS) is a systemic rheumatic autoimmune disease affecting the exocrine glandular function and is characterized by the presence of autoantibodies against the ribonucleoprotein particles, SS-A/Ro and SS-B/La, and mononuclear cell infiltration of exocrine tissues. Our aim is to characterize memory B cell pattern and function in relation to the progression of the disease, by analysing samples from a well-defined cohort of patients with primary SS. We have measured the number of Ro/La-specific plasma cells in peripheral blood mononuclear cells (PBMC) from 23 patients and 20 healthy controls by direct enzyme-linked immunospot (ELISPOT) assay. Furthermore, we quantified the Ro- and La-specific memory B cells in these individuals by a 6-day in vitro polyclonal stimulation of PBMC followed by an antigen-specific ELISPOT assay for the detection of memory B cells. In addition to this, ELISA profiling of autoantibodies was carried out using patients' plasma and supernatant, collected post-mitogen stimulation of PBMC. The average Ro60-, Ro52- and La48-specific plasma cells in PB was 9, 17 and 13 cells in 10(5) PBMC, respectively. After in vitro stimulation, these numbers increased to 43, 50 and 26 for Ro60, Ro52 and La48, correspondingly. However, the fraction of memory B cells activated into antibody-secreting cells was lower than the overall IgG B cell population. We conclude that these lower Ro/La-specific memory B cell levels may indicate that a greater portion of the Ro- and La-specific B cells are in an activated stage. This is in tune with previous reports.

Immunomodulating drugs are commonly used in treating patients with autoimmune diseases but with very different outcomes. We aimed to investigate differences in cytokine and autoantibody levels with regard to patient characteristics in patients with primary Sjögren's syndrome (pSS) receiving oral steroids or antimalarial drugs (AM) after a longer period of time.Serum samples from 141 patients fulfilling the revised EU-US criteria and 99 healthy controls were analysed for 25 cytokines and 8 autoantibodies.AM-patients had lowered levels of IL-5, IL-10, IL-13 and IFN-γ, though non-significantly. Use of prednisolone was associated with reduced levels of IL-15, IL-2, IL-4, IL-12p40, TNF-α, MIP-1α and MIP-1β (p0.05), and a trend towards decreased levels of IL-1RA and IL-1β was observed. No associations were seen between AM and antibody levels. Significantly higher protein levels of anti-Ro-52 and anti-Ro-60 were observed in the patients taking prednisolone (p0.05). The proportion of patients positive for anti-Ro-52 and anti-La-48 did not differ significantly in the groups taking and not taking prednisolone, but a difference was seen for anti-Ro-60 (p0.05).Prednisolone is a potent anti-inflammatory and immunosuppressive drug commonly used in autoimmune diseases. Our study shows that oral steroids are associated with reduced levels of several pro-inflammatory cytokines, but increased levels of pSS specific autoantibodies. The association between steroid use and increased antibody levels is not readily explained by known steroid effects, and should therefore be confirmed in further studies. Lower levels of pro-inflammatory cytokines indicate a beneficial effect of oral steroids in this patient group.

Primary Sjogren's syndrome (pSS) is a chronic autoimmune disease characterized by exocrine gland dysfunction, mainly causing sicca symptoms. B cells have a prominent role in SS, and the T follicular helper (TFH ) cells provide B cells with survival- and specialization signals in germinal centers. Here we investigate peripheral TFH cells in pSS. Sixteen pSS patients and healthy controls were enrolled in the study, with thirteen women and three men in each group. Whole blood was collected and separated into PBMC and plasma, followed by cryopreservation. Plasma samples were analyzed for Ro52, Ro60 and La48 autoantibodies by indirect ELISA. For flow cytometric analysis, we defined four subsets of TFH-like cells within the CD3+CD4+CXCR5+ population, namely the ICOS-PD1-, ICOS-PD-1+, ICOS+PD-1- and ICOS+PD-1+ ("TFH") cells. We also investigated four CD19+ B cell subsets, the CD20+CD27+CD38- memory B cells, CD20+CD27+CD38+ memory B cells, CD20-CD27+CD38++CD138- plasmablasts and CD20-CD27+CD38++CD138+ plasma cells. We observed higher fractions of ICOS+PD-1- cells, ICOS+PD-1+ ("TFH ") cells and plasmablasts in pSS patients compared to controls, and lower frequencies of both types of memory B cells. The number of TFH cells correlated positively with the levels of plasmablasts and plasma cells in the pSS patients, but not in the controls. The pSS patients were stratified according to Ro52/Ro60/La48 serology, and a positive association was found between autoantibody levels and increased level of TFH cells, plasmablasts and plasma cells and lowered levels of memory B cells. We observed a higher response to Ro/La stimulation in pSS patients compared to controls of the memory B cells, although only significantly for the CD38- memory B cells. Overall, a pathological relation between the ICOS+ T follicular-like helper cells and B cells in pSS was observed, but further work should be conducted to explore their overall impact upon disease progression. This article is protected by copyright. All rights reserved.

Dysfunctional transverse and alar craniovertebral ligaments can cause instability and osseous destruction in rheumatoid arthritis (RA). This study examined (1) the feasibility of high-resolution magnetic resonance imaging (MRI) of these ligaments in RA and (2) the relation between ligament high-signal changes and atlantoaxial subluxation and RA duration/severity. Consecutive RA patients (n = 46) underwent clinical examination, functional radiography, and high-resolution MRI. Two blinded radiologists rated MRI image quality, graded ligament high-signal changes 0–3 on proton-weighted sequences using an existing grading system, and assessed cervical spine rheumatic changes on short tau inversion recovery images. Agreement was analyzed using kappa and relations using multiple logistic regression. MRI images had good quality in 42 (91.3%) of 46 patients and were interpretable in 44 (32 women and 12 men, median age/disease duration 60.4/9.1 years). MRI grades 2–3 changes of the transverse and alar ligaments showed moderate and good interobserver agreement (kappa 0.59 and 0.78), respectively, and prevalence 31.8% and 34.1%. Such ligament changes were more frequent with increasing anterior atlantoaxial subluxation (p = 0.012 transverse, p = 0.028 alar), higher erythrocyte sedimentation rate (p = 0.003 transverse), positive rheumatoid factor (p = 0.002 alar), and neck pain (p = 0.004 alar). This first study of high-resolution MRI of these ligaments in RA showed high feasibility and relations with atlantoaxial subluxation, RA disease activity, and neck pain. The clinical usefulness of such MRI needs further evaluation.

ObjectiveSjögren's syndrome (SS) is a lymphoproliferative autoimmune disease, characterised by dryness of the mouth and eyes. Dendritic cells (DC) are potent antigen-presenting cells crucial for initiating and maintaining primary immune responses. This study quantified interferon-producing plasmacytoid DC (pDC) and two myeloid DC subsets (mDC1 and mDC2) in peripheral blood (PB) from primary SS (pSS) patients and healthy controls.MethodsBlood samples from 31 pSS patients and 28 gender and age-matched healthy controls were analysed by flow cytometry using the Miltenyi Blood DC enumeration kit. The presence of pDC in salivary glands (SG) from pSS patients was analysed by immunohistochemistry.ResultsPatients with pSS had significantly less pDC and mDC2 in PB compared with healthy controls. Moreover, pDC are present in SG from patients with pSS.ConclusionPatients with pSS have alterations among DC populations in PB, and pDC are present in the SG, suggesting a potential role of these cells in SS.

To estimate the point prevalence of primary Sjögren's syndrome (pSS) in two populations, aged 40-44 and 71-74 years, using two sets of classification criteria.The participating individuals were recruited from the Hordaland Health Study (HUSK) conducted during 1997-99. A total of 18 592 individuals born 1953-57 and 3346 individuals born 1925-27 were sent a questionnaire covering various health-related questions, including four questions about sicca symptoms. Among those answering positive to at least one of the four questions, 99 and 90 individuals born 1953-57 and 1925-27, respectively, were examined further. For diagnosis of pSS two classifications were used, the preliminary European criteria from 1993, and the revised European criteria from 1996.By using the two classification criteria from 1993 and 1996, the point prevalences were 0.44% [95% confidence interval (CI) 0.34-0.57] and 0.22% (95% CI 0.15-0.32), respectively, for the population group born 1953-57. The corresponding estimates were 3.39% (95% CI 2.77-4.14) and 1.40% (95% CI 1.02-1.92) for the population born 1925-27.The point prevalence of pSS was approximately seven times higher in the elderly population aged 71-74 years compared to individuals aged 40-44 years, regardless of the classification criteria used.

Resume Objectif Le but de cette etude etait d'evaluer dans la polyarthrite rhumatoide (PR) la proportion de patients atteignant une faible activite de la maladie apres un traitement par antifacteur necrosant des tumeurs (TNF)-α en pratique clinique. Methodes Trente-trois patients presentant une PR active malgre un traitement par methotrexate ont ete inclus dans un essai ouvert de phase IV par de l'infliximab combine a du methotrexate. La moyenne d'âge etait de 53 ans (de 21 a 71 ans) et la duree moyenne de la maladie etait de 10,7 ans (1 a 32 ans). Le traitement etait modifie en cas de reponse non satisfaisante ou d'effets secondaires majeurs. La reponse a l'infliximab etait evaluee selon les criteres de l'American College of Rheumatology (ACR 20). Le score d'activite de la maladie (DAS 28) etait etabli au debut de l'etude puis apres 26, 54, 80, 106 et 158 semaines. Une faible activite etait definie par un DAS28 ≤ 3,2. Resultats Une reponse a l'infliximab a ete notee chez 73 et 33 % des patients respectivement a la 26e et la 158e semaine. L'infliximab a ete administre de facon discontinue chez 16 patients, et 15 d'entre eux recevant alors une autre therapie anti-TNF. Un score initial DAS28 de 6,3 (intervalle de confiance (IC) : 95 % 5,9, 6,6) a ete significativement reduit a 4,1 apres 26 semaines (IC 95 % : 3,6, 4,7) et devenait quasiment stable par la suite. Un faible DAS28 a ete atteint par 36 % des patients apres 26 semaines, et par 15 a 24 % ulterieurement. Conclusions L'activite de la maladie etait significativement reduite, mais seuleument un quart des evaluations correspondaient a un DAS28 ≤ 3,2. Des travaux sont donc necessaires pour ameliorer ces resultats.

Objectives Serum cytokines play an important role in the pathogenesis of psoriatic arthritis (PsA) by initiating and perpetuating various cellular and humoral autoimmune processes. The aim of this study was to describe a broad spectrum of T- and B-cell cytokines, growth factors and chemokines in patients with PsA and healthy individuals. Methods A novel protein array system, denoted as multiplex cytokine assay was utilized to measure simultaneously the levels of 23 circulating cytokines of patients with PsA and healthy individuals. Additionally, correlational clustering and discriminant function analysis (DFA), two multivariate, supervised analysis methods were employed to identify a subset of biomarkers in order to describe potential functional inter-relationships among these pathological cytokines and identify biomarkers with prognostic and diagnostic utility. Results Univariate analysis demonstrated that serum levels of a complex set of immune and inflammatory modulating cytokines are significantly up-regulated in patients with PsA relative to unaffected controls including interleukin (IL)-10, IL-13, interferen (IFN)-alpha, epidermal growth factor (EGF), vascular endothelial growth factor (VEGF), fibroblast growth factor [CCL3 macrophage inflammatory protein (MIP)-1alpha], CCL4 (MIP-1beta) and CCL11 (Eotaxin), while granulocyte-colony stimulating factor was significantly reduced in PsA patients. Correlational clustering was able to discriminate among, and hence subclassify, patients with varying levels of disease activity, which may prove useful in guiding therapy in these apparently phenotypically distinct disease subsets. DFA identified EGF, IFN-alpha, VEGF, CCL3 (MIP-1alpha) and IL-12p40 as analytes with the strongest discriminatory power among various PsA patients and controls. Conclusions Our findings suggest that these factors modulate PsA pathology and the articular involvement in a synergistic manner. Identifying factors could be used in the development of clinical diagnostic tests, which are valuable to guide evidence-based diagnosis and disease management of PsA.

We aimed to identify the association of carotid atherosclerosis with the traditional risk factors, disease features, cytokine profile, and calprotectin in patients with primary Sjögren's syndrome (pSS).63 primary pSS patients and 63 age- and sex-matched healthy controls underwent carotid ultrasound, clinical and laboratory examination. The presence of carotid plaques was taken as carotid atherosclerosis. The covariates of carotid atherosclerosis were identified in univariate and multivariate regressions.Patients with pSS had higher prevalence of carotid atherosclerosis (13% vs. 2%, p0.05) and higher serum levels of calprotectin, tumour necrosis factor receptor 2 (TNF-R2), hepatocyte growth factor (HGF), and monocyte chemoattractant protein-1 (MCP-1) than controls. Sex, menopause, and the prevalence of traditional cardiovascular did not differ between groups (all p0.05). In univariate analyses, serum calprotectin, most traditional cardiovascular (age, male sex, metabolic syndrome, hypertension, hypertriglyceridaemia, and serum creatinine), and some disease-associated risk factors (glucocorticoid or saliva substitute use, constitutional domain of Eular-Sjögren's syndrome disease activity index - EULAR) were associated with a higher risk for plaque. In a multivariate analysis, having pSS and higher serum calprotectin were associated with carotid atherosclerosis independent of traditional risk factors.pSS have a higher prevalence of carotid atherosclerosis, which is associated with higher serum calprotectin level independent of traditional cardiovascular risk factors. Our findings suggest calprotectin as a biomarker of subclinical atherosclerosis in pSS.

Inflammation has been associated with higher cardiovascular risk in rheumatic autoimmune diseases like rheumatoid arthritis (RA) and systemic lupus erythematosus. More recently, primary Sjögren's syndrome (pSS) was also demonstrated as an independent risk factor for cardiovascular disease, emerging as a new interesting model to study atherosclerosis in autoimmune diseases. Patients with pSS have a higher prevalence of developing traditional cardiovascular risk factors like hypertension and dyslipidaemia predisposing for endothelial dysfunction and premature atherosclerosis. However, the disease-specific mechanisms for premature atherosclerosis in pSS are not fully understood. The aim of this review was to critically analyse the current literature on cardiovascular risks in pSS and to discuss the traditional and disease-associated risk factors. We also suggest possible new mechanisms that should be explored in future research to close the current knowledge gaps on the association of pSS, premature atherosclerosis, and clinical cardiovascular disease.

IntroductionSjögren's syndrome (SS) is a rheumatic autoimmune disease characterized by inflammation of exocrine glands. As autoantibodies are present in a majority of patients, B cells have been suggested to play an important role in onset and development of the disease. Toll-like receptors (TLRs) are pattern recognition receptors triggering innate immune responses. Since an increased expression of TLRs has been detected in other rheumatic diseases the purpose of this study was to explore TLRs in B cells of SS patients.MethodsThe expression of TLR-7 and -9 in B cell subsets of 25 patients with primary SS (pSS) and 25 healthy controls was analysed in peripheral blood using flow cytometry and real time quantitative PCR.ResultsWe detected similar levels of CD19+ B cells in pSS patients and healthy controls. An increased number of naïve B cells, as well as fewer pre-switched memory B cells were found in pSS patients. No significant differences were observed in TLR-7 and -9 expression in B cells between pSS patients and healthy controls.ConclusionThis study shows that pSS patients have an alteration in the B cell subpopulation composition compared to controls, with less pre-switched memory B cells and more naïve B cells. We did not detect any significant disparities in TLR-7 and -9 expression between the two groups.

Objective.The aim of this study was to investigate the clinical effect and serum markers in a cohort of rheumatoid arthritis patients with moderate to high disease activity, participating in an open clinical phase IV study conducted in Norway between 2001 and 2003 receiving infliximab treatment.Method.A total of 39 patients were studied, with a mean age of 54 years and 12-year disease duration. The analyses were performed using serum from patients at four assessment time points: baseline and 3, 6, and 12 months after starting treatment with infliximab. A wide variety of clinical data was collected and disease activity of 28 joints and Simple Disease Activity Index were calculated. The joint erosion was determined by X-ray imaging and the Sharp/van der Heijde score was determined. Serum analysis included multiplex immunoassays for 12 cytokines, 5 matrix metalloproteases, and 2 VEGFs.Results.The majority of the RA patients in this study had initially moderate to high disease activity and the infliximab treatment reduced the disease activity significantly and also reduced any further joint destruction and improved disease status. Most of the serum levels of cytokines and metalloproteases remained unchanged during the course of the study, and we were unable to detect changes in TNF-αin serum. Serum levels of IL-6 and VEGF-A decreased significantly after initiation of infliximab treatment.Conclusion.The serum levels of IL-6 and VEGF-A may be promising disease markers as they vary with disease progression. The clinical significance of these findings is yet to be determined and has to be confirmed in future clinical trials before being applied in the clinics.

The EULAR Sjögren's syndrome (SS) disease activity index (ESSDAI) is a systemic disease activity index that was designed to measure disease activity in patients with primary SS. With the growing use of the ESSDAI, some domains appear to be more challenging to rate than others. The ESSDAI is now in use as a gold standard to measure disease activity in clinical studies, and as an outcome measure, even a primary outcome measure, in current randomised clinical trials. Therefore, ensuring an accurate and reproducible rating of each domain, by providing a more detailed definition of each domain, has emerged as an urgent need. The purpose of the present article is to provide a user guide for the ESSDAI. This guide provides definitions and precisions on the rating of each domain. It also includes some minor improvement of the score to integrate advance in knowledge of disease manifestations. This user guide may help clinicians to use the ESSDAI, and increase the reliability of rating and consequently of the ability to detect true changes over time. This better appraisal of ESSDAI items, along with the recent definition of disease activity levels and minimal clinically important change, will improve the assessment of patients with primary SS and facilitate the demonstration of effectiveness of treatment for patients with primary SS.

Objective The objective of this study was to evaluate the long-term effects of anti-TNF-α treatment on temporomandibular joints (TMJs), oral mucosa, and salivary flow in RA. Study design Seventeen patients received infusions of TNF-α blocking agents after 0, 2, and 6 weeks, and then every 8 weeks until week 54 (follow-up). Clinical dysfunction index (Di) for the TMJ system, salivary flow, disease activity score (DAS28), and other medical assessments were calculated at weeks 0 and 54. Results Median Di was 5.0 (range 0-21) at baseline and 1.0 (range 0-6) (P = .001) at follow-up. Mean salivary flow was 3.2 mL/15 minutes at baseline and 4.6 at follow-up (P = .055). Two (11.7%) of the patients developed oral candidiasis during the period of treatment. The median DAS28 was 6.2 (range, 4.7-7.7) at baseline and 4.1 (range, 1.6-6.8) at follow-up (P = .001). Conclusion We conclude that anti-TNF-α blocking treatments have beneficial effects on oral as well as general manifestations of RA.