Bicaudal D2 autoantibodies are highly specific for systemic sclerosis.

OBJECTIVE: Autoantibodies directed against the intracellular protein bicaudal D2 (BICD2) have been identified as a specific marker of systemic sclerosis (SSc). Since autoantibodies are of value in predicting disease onset and identifying meaningful clinical subsets, as well as having prognostic value, this study aimed to establish the prevalence of BICD2 autoantibodies (anti-BICD2) in a cohort of patients with connective tissue disease and healthy controls. METHOD: In this cross-sectional study, 363 patients with connective tissue disease (121 SSc, 141 systemic lupus erythematosus, 101 myositis, and 100 blood donors) were tested for the presence of anti-BICD2. All SSc patients were tested for specific anti-nuclear antibodies (ANAs), and clinical and laboratory associations were evaluated in the SSc patients, stratified by anti-BICD2 status. RESULTS: In the SSc cohort, 35 patients had autoantibodies directed against BICD2. The specificity of anti-BICD2 in SSc patients was 96.5%; however, the sensitivity was only 28.9%. Anti-BICD2 and centromere autoantibodies were present together in 91% of the anti-BICD2-positive SSc patients, and in none of the cases was anti-BICD2 the only antibody present. Anti-BICD2-positive patients had lower forced expiratory volume in 1 s (FEV1) (p = 0.01) and lower carbon monoxide transfer coefficient (KCO) (p = 0.01) than anti-BICD2-negative SSc patients, but they had higher forced vital capacity (p = 0.03). CONCLUSION: Autoantibodies against BICD2 were highly specific for SSc patients. Reduced FEV1 and KCO in anti-BICD2-positive patients may indicate that the presence of anti-BICD2 is associated with altered lung function in an unknown pathophysiological manner, which awaits further elucidation.

Effectiveness, safety and impact of guselkumab on sexuality and perceived stigmatization in patients with psoriasis in routine clinical practice: Week 28 results from the prospective German multicentre G-EPOSS study.

BACKGROUND: G-EPOSS is a prospective, non-interventional, German multicentre study of patients with moderate-to-severe plaque psoriasis receiving guselkumab, a therapeutic monoclonal antibody targeting interleukin-23, in a real-world setting. OBJECTIVES: The objective of the study was to evaluate the effectiveness and safety of guselkumab, including its impact on skin, health-related quality of life (HRQoL), sexuality, and perceived stigmatization. METHODS: Patients (≥18 years old) received guselkumab per routine clinical practice. The primary endpoint was the proportion of patients achieving absolute Psoriasis Area and Severity Index (PASI) ≤ 3 at Week (W)28. Secondary endpoint assessments over 28 weeks included the Nail Psoriasis Severity Index (NAPSI), anogenital Physician's Global Assessment (aPGA), and Dermatology Life Quality Index (DLQI). Sexuality and perceived stigmatization were assessed by patients using the Relationship and Sexuality Scale (RSS) and Perceived Stigmatization Questionnaire (PSQ), respectively. RESULTS: Overall, 293 patients were included in the evaluable set population. Mean age and disease duration were 45.6 and 17.6 years, respectively. At baseline, mean PASI, aPGA and DLQI scores were 15.3, 2.7 and 11.3, respectively. In total, 25.9% of patients had received a prior biologic. Overall, 83.0% of patients achieved PASI ≤ 3, and 56.2%/35.1% achieved PASI ≤ 1/PASI = 0, respectively, at W28. Among those with NAPSI ≥ 1 and aPGA ≥ 1 at baseline, NAPSI = 0 and aPGA = 0 were achieved by 39.2% and 61.1% of patients, respectively, and 61.4% of patients achieved DLQI 0-1 at W28. Improvements were observed over 28 weeks across individual items of the DLQI, RSS and PSQ, indicating improved HRQoL and sex life, and decreased perceived stigmatization. Based on DLQI Question (Q)9, 53.6% of patients experienced sexual difficulties at baseline, which decreased to 12.1% at W28. DLQI Q9 responses were consistent with RSS item responses, highlighting DLQI Q9 as a sentinel for sexual impairment. CONCLUSIONS: Guselkumab improved overall skin symptoms and HRQoL in patients with psoriasis and decreased sexual impairment and perceived stigmatization. No new safety signals were observed. STUDY CODE: CNTO1959PSO4008.

Effective protein extraction combined with data independent acquisition analysis reveals a comprehensive and quantifiable insight into the proteomes of articular cartilage and subchondral bone.

OBJECTIVE: The objectives of this study was to establish a sensitive and reproducible method to map the cartilage and subchondral bone proteomes in quantitative terms, and mine the proteomes for proteins of particular interest in the pathogenesis of osteoarthritis (OA). The horse was used as a model animal. DESIGN: Protein was extracted from articular cartilage and subchondral bone samples from three horses in triplicate by pressure cycling technology or ultrasonication. Digested proteins were analysed by data independent acquisition based mass spectrometry. Data was processed using a pre-established spectral library as reference database (FDR 1%). RESULTS: We identified to our knowledge the hitherto most comprehensive quantitative cartilage (1758 proteins) and subchondral bone (1482 proteins) proteomes in all species presented to date. Both extraction methods were sensitive and reproducible and the high consistency of the identified proteomes (>97% overlap) indicated that both methods preserved the diversity among the extracted proteins. Proteome mining revealed a substantial number of quantifiable cartilage and bone matrix proteins and proteins involved in osteogenesis and bone remodeling, including ACAN, BGN, PRELP, FMOD, COMP, ACP5, BMP3, BMP6, BGLAP, TGFB1, IGF1, ALP, MMP3, and collagens. A number of proteins, including COMP and TNN, were identified in different protein isoforms with potential unique biological roles. CONCLUSION: We have successfully developed two sensitive and reproducible non-species specific workflows enabling a comprehensive quantitative insight into the proteomes of cartilage and subchondral bone. This facilitates the prospect of investigating the molecular events at the osteochondral unit in the pathogenesis of OA in future projects.

Birthweight, body size, and growth during childhood and risks of rheumatoid arthritis: a large Danish cohort study.

OBJECTIVES: Adult obesity may be positively associated with risks of rheumatoid arthritis (RA), but associations with early life body size are unknown. We examined whether birthweight, childhood body mass index (BMI), height, and changes in BMI and height were associated with risks of adult RA. METHOD: A cohort of 346 602 children (171 127 girls) from the Copenhagen School Health Records Register, born in 1930-1996, with measured weights and heights from 7 to 13 years of age, were included. Information on RA, including serological status, came from national registers from 1977 to 2017. Cox regressions were performed. RESULTS: During a median of 35.1 years of observation time per person, 4991 individuals (3565 women) were registered with RA. Among girls, per BMI z-score, risks of RA and seropositive RA increased by 4-9% and 6-10%, respectively. Girls with overweight had higher risks of RA than girls without overweight. Girls who became overweight by 13 years of age had increased risks of RA compared to girls without overweight at 7 or 13 years (hazard ratio = 1.40, 95% confidence interval 1.19-1.66). For boys, associations between BMI and RA (including seropositive RA) were not statistically significant. Height was not associated with RA (any type) in girls. Taller boys had higher risks of RA, especially seropositive RA. Birthweight was not associated with RA. CONCLUSIONS: Among women, childhood adiposity was associated with increased risks of RA. Among men, childhood height was positively associated with risks of RA. These findings support the hypothesis that early life factors may be important in the aetiology of RA.

Stem cell concepts in myelodysplastic syndromes: lessons and challenges.

According to the cancer stem cell (CSC) hypothesis, CSCs are the only cancer cells that can give rise to and sustain all cells that constitute a cancer as they possess inherent or acquired self-renewal potential, and their elimination is required and potentially sufficient to achieve a cure. Whilst establishing CSC identity remains challenging in most cancers, studies of low-intermediate risk myelodysplastic syndromes (MDS), other chronic myeloid malignancies and clonal haematopoiesis of indeterminant potential (CHIP) strongly support that the primary target cell usually resides in the rare haematopoietic stem cell (HSC) compartment. This probably reflects the unique self-renewal potential of HSCs in normal human haematopoiesis, combined with the somatic initiating genomic driver lesion not conferring extensive self-renewal potential to downstream progenitor cells. Mutational 'fate mapping' further supports that HSCs are the only disease-propagating cells in low-intermediate risk MDS, but that MDS-propagating potential might be extended to progenitors upon disease progression. The clinical importance of MDS stem cells has been highlighted through the demonstration of selective persistence of MDS stem cells in patients at complete remission in response to therapy. This implies that MDS stem cells might possess unique resistance mechanisms responsible for relapses following otherwise efficient treatments. Specific surveillance of MDS stem cells should be considered to assess the efficiency of therapies and as an early indicator of emerging relapses in patients in clinical remission. Moreover, further molecular characterization of purified MDS stem cells should facilitate identification and validation of improved and more stem cell-specific therapies for MDS.

Microvesicles in active lupus nephritis show Toll-like receptor 9-dependent co-expression of galectin-3 binding protein and double-stranded DNA.

Circulating microvesicles (MVs) from patients with systemic lupus erythematosus (SLE) express the type 1 interferon (IFN)-inducible protein galectin-3 binding protein (G3BP), which may enhance their deposition in the glomerular basement membrane. The release of G3BP-expressing MVs from normal peripheral blood mononuclear cells (PBMCs) is induced by Toll-like receptor 9 (TLR-9) ligands, and these vesicles contain autoantibody-accessible double-stranded DNA (dsDNA). This study compares the release of MVs expressing G3BP and dsDNA from PBMCs derived from SLE patients with or without active lupus nephritis (LN) and from healthy donors, and taps further into the potential dependency on IFN-α for their generation and impacts of TLR-7/TLR-9 co-stimulation. PBMCs from 10 healthy donors and 12 SLE patients, six of whom had active LN at study inclusion, were stimulated in-vitro with recombinant human IFN-α and the TLR-9 agonists oligodeoxynucleotide (ODN)2216 or ODN2395 alone or in combination with the TLR-7 agonist gardiquimod. MVs in the supernatants were subsequently isolated by differential centrifugation and their expression of G3BP and dsDNA was quantified by flow cytometry. Stimulation with ODN2395 significantly increased the release of MVs co-expressing G3BP and dsDNA from PBMCs isolated from healthy donors and SLE patients. The expression of G3BP on individual MVs and the proportion of G3BP and dsDNA double-positive MVs released were increased in active LN patients. Neither co-stimulation with gardiquimod nor with the IFN-α inhibitor IN-1 had any effect on the MV release induced by ODN2395. In conclusion, the TLR-9-mediated inducibility of MVs co-expressing G3BP and dsDNA is increased in SLE patients with active LN.

Lymphopenia and neutropenia are associated with subsequent incident proteinuria in Danish patients with systemic lupus erythematosus.

Objective: The aim of this study was to investigate whether incident proteinuria in patients with systemic lupus erythematosus (SLE) was preceded by changes in blood lymphocytes and neutrophil counts and/or neutrophil-lymphocyte ratio (NLR).Method: SLE patients with no proteinuria before or at the time of classification were included. Longitudinal data on SLE manifestations, vital status, and SLE-associated medications were collected during clinical visits and chart review. Laboratory data were collected through a nationwide database. Lymphopenia, severe lymphopenia, and neutropenia were defined as values below 0.8 × 109, 0.5 × 109, and 2.0 × 109 cells/L, respectively. High NLR was defined as values above the median. Proteinuria was defined by at least two measurements of elevated urine protein excretion (> 0.5 g/day). Hazard ratios (HRs) were calculated by Cox modelling using time-dependent continuous and binary covariates based on multiple laboratory measurements adjusted for use of immunosuppressants.Results: In total, 260 SLE patients were available for the analysis, of whom 30 (12%) developed incident proteinuria following the diagnosis of SLE. Median follow-up time was 73.5 months. Lymphocyte and neutrophil counts, but not NLR, were associated with incident proteinuria. HRs for incident proteinuria were 2.71 for lymphopenia [95% confidence interval (CI) 1.20-6.11], 4.73 for severe lymphopenia (95% CI 1.93-11.59), and 2.54 for neutropenia (95% CI 1.14-5.65).Conclusion: Lymphopenia and neutropenia predicted the risk of first-time proteinuria independently of immunosuppressants.

Chronic hyponatremia and association with osteoporosis among a large racially/ethnically diverse population.

Chronic hyponatremia may contribute to decreased bone density. We studied 341,003 men and women who underwent DXA testing and observed that individuals with chronic hyponatremia (sodium < 135 mEq/L) had an 11% greater likelihood of having osteoporosis. There was a dose-dependent effect with lower sodium and stronger association with osteoporosis. INTRODUCTION: Chronic hyponatremia has been associated with both neurologic deficits and increased risk of gait abnormalities leading to falls and resultant bone fractures. Whether chronic hyponatremia contributes to decreased bone density is uncertain. We evaluated whether chronic, mild hyponatremia based on serial sodium measurements was associated with increased risk of osteoporosis within a large, ethnically diverse population. METHODS: This is a retrospective cohort study between January 1, 1998 and December 31, 2014 within Kaiser Permanente Southern California, an integrated healthcare delivery system. Men and women were aged ≥ 55 years with ≥ 2 serum sodium measurements prior to dual-energy X-ray absorptiometry (DXA) testing. Time-weighted (TW) mean sodium values were calculated by using the proportion of time (weight) elapsed between sodium measurements and defined as < 135 mEq/L. Osteoporosis defined as any T-score value ≤ - 2.5 of lumbar spine, femoral neck, or hip. RESULTS: Among 341,003 individuals with 3,330,903 sodium measurements, 11,539 (3.4%) had chronic hyponatremia and 151,505 (44.4%) had osteoporosis. Chronic hyponatremic individuals had an osteoporosis RR (95% CI) of 1.11 (1.09, 1.13) compared to those with normonatremia. A TW mean sodium increase of 3 mEq/L was associated with a lower risk of osteoporosis [adjusted RR (95% CI) 0.95 (0.93, 0.96)]. A similar association was observed when the arithmetic mean sodium value was used for comparison. CONCLUSIONS: We observed a modest increase in risk for osteoporosis in people with chronic hyponatremia. There was also a graded association between higher TW mean sodium values and lower risk of osteoporosis. Our findings underscore the premise that chronic hyponatremia may lead to adverse physiological effects and responses which deserves better understanding.

Peptidylarginine deiminase-4 gene polymorphisms are associated with systemic lupus erythematosus and lupus nephritis.

OBJECTIVE: Peptidylarginine deiminase-4 (PAD4) is highly expressed by neutrophils and essential for citrullination occurring during the formation of neutrophil extracellular traps, which have been implicated in the pathogenesis of systemic lupus erythematosus (SLE) and lupus nephritis (LN). Single-nucleotide polymorphisms (SNPs) in PADI4 influence PAD4 expression and functionality. Here, we investigate whether SNPs in PADI4 influence the risk of SLE or LN. METHOD: Altogether, 234 SLE patients and 484 controls were genotyped for nine PADI4 SNPs known to alter PAD4 functionality and/or expression, or to be associated with other autoimmune diseases, using an in-house multiplex Luminex assay. All analyses were adjusted for age and gender. RESULTS: Heterozygosity for rs1748033, and heterozygosity and homozygosity for rs1635564, were associated with increased occurrence of SLE [odds ratio (OR) 1.55, 95% confidence interval (CI) 1.08-2.23; OR 1.52, 95% CI 1.06-2.19; and OR 2.06, 95% CI 1.08-3.93, respectively]. Homozygosity for rs1635564 was also associated with increased occurrence of LN (OR 3.35, 95% CI 1.2-10.97). Notably, gene dose effects of the rs1635564 variant allele were observed for SLE (p = 0.005) and LN (p = 0.01). Carriage of minor alleles of five other SNPs (rs11203366, rs11203367, rs874881, rs2240340, and rs11203368) was associated with increased occurrence of LN and hypertension. CONCLUSION: The rs1635564 polymorphism of PADI4 is a candidate risk factor for SLE, particularly with renal involvement. Additional PADI4 polymorphisms also conferred increased risk of LN. Overall, these findings support the notion of PAD4 contributing to the pathogenesis of SLE and LN.

Anti-cyclic citrullinated peptide antibodies, 28-joint Disease Activity Score, and magnetic resonance imaging bone oedema at baseline predict 11 years' functional and radiographic outcome in early rheumatoid arthritis.

OBJECTIVE: To investigate the clinical and radiographic status, and to identify baseline predictors of functional status and erosive progression at 11 years' follow-up of early rheumatoid arthritis (RA) patients. METHODS: Patients enrolled in the Danish investigator-initiated randomized controlled CIMESTRA trial, which investigated a 2 year treat-to-target intervention with methotrexate and intra-articular glucocorticoids with or without cyclosporine, were followed up. The 28-joint Disease Activity Score (DAS28), Health Assessment Questionnaire (HAQ) score, and total Sharp van der Heijde score (TSS) were assessed at baseline and 11 years. Baseline magnetic resonance imaging (MRI) of unilateral wrists was scored (OMERACT RAMRIS). Multivariable linear regression analyses of baseline variables [TSS, HAQ, DAS28, age, anti-cyclic citrullinated peptide (anti-CCP) status, gender, MRI erosion score, MRI synovitis score, MRI bone marrow oedema score] were performed in 96 patients with HAQ11yrs and ∆TSS0-11yrs as dependent variables. Since outcomes were similar in the two treatment arms, data were pooled. RESULTS: In total, 120 of 160 patients completed 11 years' follow-up. They were 63 (55-72) years old, 68% were in DAS28 remission (≤ 2.4), HAQ11yrs was 0.25 (0-0.75), mean ∆TSS0-11yrs was 0.96 ± 1.52 units/year; 53%, 20%, and 27% received conventional treatment, biologics, and no treatment, respectively; and 34% had not progressed radiographically since baseline. Increased DAS28 (p = 0.02) and anti-CCP (p = 0.03) predicted HAQ11yrs, whereas anti-CCP (p = 0.03) and MRI bone marrow oedema (p = 0.01) predicted ∆TSS0-11yrs in multivariable analyses. CONCLUSIONS: Early and strict synovitis suppression with methotrexate and intra-articular glucocorticoids led to persistently high remission rates and limited erosive progression at 11 years. In this well-treated cohort, baseline anti-CCP status, DAS28, and MRI bone marrow oedema predicted functional status and/or erosive progression.

Plasma levels of ß2-microglobulin are associated with atherosclerosis in patients with systemic lupus erythematosus: a cross-sectional cohort study.

Objective The objective of this paper is to examine the association between plasma levels of ß2-microglobulin (ß2MG), a protein previously associated with atherosclerosis, and the presence of carotid plaque (CP) or coronary artery calcium (CAC) in a cross-sectional cohort study of patients with systemic lupus erythematosus (SLE). Methods Patients with SLE were enrolled between June 2013 and May 2014. The presence of CP and CAC was assessed with ultrasonography and computed tomography scan, respectively. The presence of CP or CAC in the SLE patients was analyzed with respect to plasma levels of ß2MG and renal function expressed as the estimated glomerular filtration rate (eGFR). Results The study cohort consisted of 147 patients, 89% women and 95% Caucasians. The median age was 46 (range: 21-75) years with a median disease duration of 14 years. CP and CAC was observed in 29 (20%) and 57 (39%) of patients, respectively. CP or CAC was seen in 62 (42%) patients and was associated with the highest quartile of plasma ß2MG in patients with eGFR ≥ 90 ml/min/1.73 m2; OR = 18 (95% CI: 1.7-181). ß2MG adjusted for eGFR was also associated with presence of CP or CAC in the total cohort. The exclusion of 25 patients with a prior history of cardiovascular disease did not change the observed associations. Conclusion In this study, we found significant associations between imaging markers of atherosclerosis and high plasma levels of plasma ß2MG. These data suggest that ß2MG is a candidate for further study as a biomarker for atherosclerosis in SLE.

Circulating serum interleukin-6, serum chitinase-3-like protein-1, and plasma vascular endothelial growth factor are not predictive for remission and radiographic progression in patients with early rheumatoid arthritis: post-hoc explorative and validation studies based on the CIMESTRA and OPERA trials.

OBJECTIVE: To investigate serum interleukin-6 (IL-6), serum chitinase-3-like protein-1 (YKL-40), and plasma vascular endothelial growth factor (VEGF) as measures of disease activity and predictors of clinical remission and radiographic progression in two early rheumatoid arthritis (RA) randomized controlled trials (RCTs). METHOD: Treatment-naïve patients with early RA (< 6 months' duration) and active disease, participating in two investigator-initiated RCTs, were treated according to a predefined treat-to-target algorithm aiming at inflammatory control, using methotrexate (MTX) + cyclosporine versus MTX + placebo (CIMESTRA study, n = 150, 5 year follow-up) or MTX + adalimumab versus MTX + placebo (OPERA study, n = 180, 2 year follow-up). The 28-joint Disease Activity Score (DAS28) and conventional radiography [bilateral hands and feet at baseline, 2 years and 5 years (only CIMESTRA)] were obtained at baseline and during follow-up. Serum IL-6, serum YKL-40, and plasma VEGF were measured in baseline blood samples and during follow-up. Hypotheses regarding the biomarkers' relation with DAS28 and ability to predict clinical remission (DAS28 < 2.6) and radiographic progression (change in total Sharp van der Heijde score ≥ 2) were generated in CIMESTRA and validated in OPERA, by Spearman's correlation and logistic regression analyses. RESULTS: Baseline IL-6, YKL-40, and VEGF correlated significantly with DAS28 in CIMESTRA (r = 0.50, r = 0.36, r = 0.36, respectively, all p < 0.01) and these results were confirmed in OPERA patients (r = 0.52, p < 0.01; r = 0.18, p = 0.01; r = 0.23, p = 0.002, respectively). None of the biomarkers (absolute values or change) was predictive of clinical remission or radiographic progression at 2 or 5 years in either study. CONCLUSION: Serum IL-6, serum YKL-40, and plasma VEGF were significantly correlated with DAS28 at baseline, but did not have consistent predictive value for clinical remission or radiographic progression in two early RA RCTs.

Correction to: Inflammatory markers before and after farrowing in healthy sows and in sows affected with postpartum dysgalactia syndrome.

The original article [1] contains an error whereby the caption in Figure 8 is incorrect; the correct caption can be seen ahead alongside its respective image.

Increased glucose-stimulated FGF21 response to oral glucose in obese nondiabetic subjects after Roux-en-Y gastric bypass.

OBJECTIVE: The positive metabolic outcome of Roux-en-Y gastric bypass (RYGB) surgery may involve fibroblast growth factor 21 (FGF21), in both the fasting state and postprandially. We measured the fasting levels of FGF21 before and after bariatric surgery as well as the postprandial FGF21 responses after a glucose load and after a mixed meal. DESIGN: Observational intervention trial. PATIENTS AND MEASUREMENTS: Eight obese, nondiabetic patients underwent RYGB. Plasma FGF21 was measured both before and after surgery on three different days during oral glucose loads (25 g or 50 g glucose) or a mixed meal. Blood samples were taken right before the meal and at 15-min intervals until 90 min and at 150 min and 210 min relative to the start of the meal. RESULTS: Overall, fasting plasma FGF21 did not change significantly before and after surgery (262 ± 71 vs 411 ± 119 pg/ml), but for three subjects, fasting plasma FGF21 increased significantly after surgery. Furthermore, FGF21 levels increased significantly at t = 90 and t = 150 min in response to 50 g glucose, but not after a mixed meal. CONCLUSIONS: In conclusion, the observed increase in postprandial plasma FGF21 in response to glucose and the lack of FGF21 response to a mixed meal may have important implications for the physiologic role of FGF21. The increase in postprandial FGF21 in response to glucose in the early postoperative period may contribute to the metabolic improvements observed after gastric bypass.

Treatment with belimumab in systemic lupus erythematosus does not impair antibody response to 13-valent pneumococcal conjugate vaccine.

Background/purpose The objective of this study was to explore the impact of systemic lupus erythematosus and belimumab given in addition to standard of care therapy on 13-valent conjugated pneumococcal vaccine (PCV13) response. Methods Forty-seven systemic lupus erythematosus patients and 21 healthy controls were immunized with a single dose of 13-valent conjugated pneumococcal vaccine. Forty systemic lupus erythematosus patients were treated with traditional disease-modifying anti rheumatic drugs, 11 of those received belimumab in addition, and 32 patients were treated with concomitant prednisolone. Quantification of serotype specific IgG levels to 12 pneumococcal capsular polysaccharides was performed in serum taken before and four to six weeks after vaccination using multiplex fluorescent microsphere immunoassay. IgG levels against serotypes 23F and 6B were also analyzed using standard enzyme-linked immunosorbent assays. Opsonophagocytic assay was performed on serotype 23F to evaluate the functionality of the antibodies. Pre- and post-vaccination log transformed antibody levels were compared to determine the impact of systemic lupus erythematosus diagnosis and different treatments on antibody response. Results Systemic lupus erythematosus patients as a group showed lower post-vaccination antibody levels and lower fold increase of antibody levels after vaccination compared to controls ( p = 0.02 and p = 0.009, respectively). Systemic lupus erythematosus patients treated with belimumab in addition to standard of care therapy or with only hydroxychloroquine did not differ compared to controls, whereas the other treatment groups had significantly lower fold increase of post-vaccination antibody levels. Higher age was associated with lower post-vaccination antibody levels among systemic lupus erythematosus patients. Conclusion Belimumab given in addition to traditional disease-modifying anti rheumatic drugs or prednisolone did not further impair antibody response to 13-valent conjugated pneumococcal vaccine.

Breast cancer in systemic lupus.

Objective There is a decreased breast cancer risk in systemic lupus erythematosus (SLE) versus the general population. We assessed a large sample of SLE patients, evaluating demographic and clinical characteristics and breast cancer risk. Methods We performed case-cohort analyses within a multi-center international SLE sample. We calculated the breast cancer hazard ratio (HR) in female SLE patients, relative to demographics, reproductive history, family history of breast cancer, and time-dependent measures of anti-dsDNA positivity, cumulative disease activity, and drugs, adjusted for SLE duration. Results There were 86 SLE breast cancers and 4498 female SLE cancer-free controls. Patients were followed on average for 7.6 years. Versus controls, SLE breast cancer cases tended to be white and older. Breast cancer cases were similar to controls regarding anti-dsDNA positivity, disease activity, and most drug exposures over time. In univariate and multivariate models, the principal factor associated with breast cancers was older age at cohort entry. Conclusions There was little evidence that breast cancer risk in this SLE sample was strongly driven by any of the clinical factors that we studied. Further search for factors that determine the lower risk of breast cancer in SLE may be warranted.

The prevalence and determinants of anti-DFS70 autoantibodies in an international inception cohort of systemic lupus erythematosus patients.

Autoantibodies to dense fine speckles 70 (DFS70) are purported to rule out the diagnosis of SLE when they occur in the absence of other SLE-related autoantibodies. This study is the first to report the prevalence of anti-DFS70 in an early, multinational inception SLE cohort and examine demographic, clinical, and autoantibody associations. Patients were enrolled in the Systemic Lupus International Collaborating Clinics (SLICC) inception cohort within 15 months of diagnosis. The association between anti-DFS70 and multiple parameters in 1137 patients was assessed using univariate and multivariate logistic regression. The frequency of anti-DFS70 was 7.1% (95% CI: 5.7-8.8%), while only 1.1% (95% CI: 0.6-1.9%) were monospecific for anti-DFS70. In multivariate analysis, patients with musculoskeletal activity (Odds Ratio (OR) 1.24 [95% CI: 1.10, 1.41]) or with anti-ß2 glycoprotein 1 (OR 2.17 [95% CI: 1.22, 3.87]) were more likely and patients with anti-dsDNA (OR 0.53 [95% CI: 0.31, 0.92]) or anti-SSB/La (OR 0.25 [95% CI: 0.08, 0.81]) were less likely to have anti-DFS70. In this study, the prevalence of anti-DFS70 was higher than the range previously published for adult SLE (7.1 versus 0-2.8%) and was associated with musculoskeletal activity and anti-ß2 glycoprotein 1 autoantibodies. However, 'monospecific' anti-DFS70 autoantibodies were rare (1.1%) and therefore may be helpful to discriminate between ANA-positive healthy individuals and SLE.

A fluorescence sedimentation assay for dsDNA antibodies.

The Farr assay is a radioimmunoassay (RIA) for dsDNA antibodies, based on antibody precipitation using ammonium sulphate and quantification using radio-labelled dsDNA. The RIA-Farr assay offers outstanding clinical specificity and sensitivity for systemic lupus erythematosus (SLE) compared to other assays but does also present some disadvantages as it utilizes radioactive-labelled dsDNA and requires high levels of technical expertise for safe handling. Here, a new precipitation assay, 'Fluoro-Farr' assay, is described. This assay maintains a high sensitivity and specificity for SLE but is based on precipitation with polyethylene glycol (PEG) and fluorescence of EvaGreen intercalated in dsDNA as detection principle. As dsDNA antibodies are quantified using fluorescence, the disadvantages of working with radioactivity are eliminated. The Fluoro-Farr assay was developed and validated, and the diagnostic efficiency of the assay was evaluated by testing 57 sera from SLE patients and 60 healthy controls. The Fluoro-Farr assay revealed a diagnostic sensitivity of 68% at a diagnostic specificity of 95% (ROC AUC 0.91). Furthermore, the new Fluoro-Farr assay was compared to the RIA-Farr assay, and showed a correlation of the outcomes from the two assays, but the Fluoro-Farr assay did not outperform the RIA-Farr assay due to its outstanding clinical diagnostic efficiency (ROC AUC 0.99). In conclusion, the Fluoro-Farr assay presents a viable alternative to the traditional RIA-Farr assay; especially in laboratories without facilities to perform assays with radioactivity-based read-out. As the RIA-Farr assay, the Fluoro-Farr assay has the advantage of being a precipitation assay allowing antibody:dsDNA interaction in solution using native dsDNA.

Steep rise in norovirus cases and emergence of a new recombinant strain GII.P16-GII.2, Germany, 2016.

Since early November 2016, the number of laboratory-confirmed norovirus infections reported in Germany has been increasing steeply. Here, we report the detection and genetic characterisation of an emerging norovirus recombinant, GII.P16-GII.2. This strain was frequently identified as the cause of sporadic cases as well as outbreaks in nine federal states of Germany. Our findings suggest that the emergence of GII.P16-GII.2 contributed to rising case numbers of norovirus gastroenteritis in Germany.

Humoral markers of active Epstein-Barr virus infection associate with anti-extractable nuclear antigen autoantibodies and plasma galectin-3 binding protein in systemic lupus erythematosus.

We investigated if signs of active Epstein-Barr virus and cytomegalovirus infections associate with certain autoantibodies and a marker of type I interferon activity in patients with systemic lupus erythematosus. IgM and IgG plasma levels against Epstein-Barr virus early antigen diffuse and cytomegalovirus pp52 were applied as humoral markers of ongoing/recently active Epstein-Barr virus and cytomegalovirus infections, respectively. Plasma galectin-3 binding protein served as a surrogate marker of type I interferon activity. The measurements were conducted in 57 systemic lupus erythematosus patients and 29 healthy controls using ELISAs. Regression analyses and univariate comparisons were performed for associative evaluation between virus serology, plasma galectin-3 binding protein and autoantibodies, along with other clinical and demographic parameters. Plasma galectin-3 binding protein concentrations were significantly higher in systemic lupus erythematosus patients (P = 0.009) and associated positively with Epstein-Barr virus early antigen diffuse-directed antibodies and the presence of autoantibodies against extractable nuclear antigens in adjusted linear regressions (B = 2.02 and 2.02, P = 0.02 and P = 0.002, respectively). Furthermore, systemic lupus erythematosus patients with anti-extractable nuclear antigens had significantly higher antibody levels against Epstein-Barr virus early antigen diffuse (P = 0.02). Our study supports a link between active Epstein-Barr virus infections, positivity for anti-extractable nuclear antigens and increased plasma galectin-3 binding protein concentrations/type I interferon activity in systemic lupus erythematosus patients.