The tellurium-based immunomodulator, AS101 ameliorates adjuvant-induced arthritis in rats.

Despite undeniable improvement in the management of rheumatoid arthritis (RA), the discovery of more effective, less toxic and, ideally, less immune suppressive drugs are much needed. In the current study, we set to explore the potential anti-rheumatic activity of the non-toxic, tellurium-based immunomodulator, AS101 in an experimental animal model of RA. The effect of AS101 was assessed on adjuvant-induced arthritis (AIA) rats. Clinical signs of arthritis were assessed. Histopathological examination was used to assess inflammation, synovial changes and tissue lesions. Very late antigen-4 (VLA-4)+ cellular infiltration was detected using immunohistochemical staining. Enzyme-linked immunosorbent assay (ELISA) was used to measure circulating anti-cyclic citrullinated-peptide autoantibody (ACPA) and real-time polymerase chain reaction (PCR) was used to measure the in-vitro effect of AS101 on interleukin (IL)-6 and IL-1ß expression in activated primary human fibroblasts. Prophylactic treatment with intraperitoneal AS101 reduced clinical arthritis scores in AIA rats (P < 0·01). AS101 abrogated the migration of active chronic inflammatory immune cells, particularly VLA-4+ cells, into joint cartilage and synovium, reduced the extent of joint damage and preserved joint architecture. Compared to phosphate-buffered saline (PBS)-treated AIA rats, histopathological inflammatory scores were significantly reduced (P < 0·05). Furthermore, AS101 resulted in a marked reduction of circulating ACPA in comparison to PBS-treated rats (P < 0·05). Importantly, AS101 significantly reduced mRNA levels of proinflammatory mediators such as IL-6 (P < 0·05) and IL-1ß (P < 0·01) in activated primary human fibroblasts. Taken together, we report the first demonstration of the anti-rheumatic/inflammatory activity of AS101 in experimental RA model, thereby supporting an alternative early therapeutic intervention and identifying a promising agent for therapeutic intervention.

IVIG ameliorate inflammation in collagen-induced arthritis: projection for IVIG therapy in rheumatoid arthritis.

Rheumatoid arthritis (RA) is a systemic inflammatory autoimmune disease that leads to joint destruction and disability. Despite a significant progress in administration of biological agents for RA patients, there is still a need for improved therapy. Intravenous immunoglobulins (IVIG), a pooled polyspecific immunoglobulin (Ig)G extracted from 5000 to 20 000 healthy subjects, showed beneficial therapeutic effect in patients with immune deficiency, sepsis and autoimmune diseases. The current study aimed to investigate the beneficial effect of treatment with IVIG in established collagen-induced arthritis in DBA/1j mice. Murine arthritis was induced in DBA/1j mice. Treatment with IVIG began when the disease was established. The clinical score was followed twice a week until day 48. The mice were bled for plasma and the paws were hematoxylin and eosin (H&E)-stained. Cytokine profile in the plasma was analyzed by Luminex technology and titers of circulating anti-collagen antibodies in the plasma was tested by enzyme-linked immunosorbent assay. Our results show that treatment with IVIG in murine significantly reduced the clinical arthritis score (P < 0·001). Moreover, mode of action showed that IVIG significantly reduced circulating levels of inflammatory cytokines [interferon (IFN)-γ, interleukin (IL)-1ß, IL-17, IL-6, tumor necrosis factor (TNF)-α, P < 0·001], inhibiting anti-collagen antibodies (P < 0·001) in the plasma of collagen-induced arthritis mice. Importantly, histopathological examination revealed that IVIG treatment prevented the migration of inflammatory immune cells into the cartilage and synovium, reduced the extent of joint damage and preserved joint architecture. Our results proved for the first time the valuable anti-inflammatory treatment of IVIG in experimental RA. We propose IVIG therapy for a subgroup of patients with rheumatologically related diseases.

Adherence to metformin and the onset of rheumatoid arthritis: a population-based cohort study.

Objective: The aim of this retrospective cohort study was to examine whether adherence to metformin treatment may be associated with lower onset of rheumatoid arthritis (RA).Method: Using the computerized databases of a 2.3-million state-mandated health services organization in Israel, we identified incident RA cases among a cohort of 113 749 adult patients who initiated metformin therapy between 1998 and 2014. Adherence was assessed by calculating the mean proportion of follow-up days covered (PDC) with metformin.Results: During the 18 year study period, there were 558 incident RA cases (61 per 100 000 person-years). Adherence to metformin treatment was associated with a lower risk of developing RA, with the lowest risk recorded among patients with a PDC of 40-59% [adjusted hazard ratio (HR) 0.62, 95% confidence interval (CI) 0.45-0.84] compared with non-adherent patients (PDC < 20%). A mean daily metformin dose of 2550 mg or more was also associated with a lower risk of developing RA (adjusted HR 0.62, 95% CI 0.46-0.84) compared to a daily dose of 850 mg or less. In stratified analyses by gender, the negative association between adherence and the risk of RA was limited to women alone.Conclusions: Adherence to metformin treatment is associated with a reduced risk of developing RA in women. Further studies are needed to assess the effect of metformin on RA development in other patient populations.

Immunoglobulin A antibodies to oxidized collagen type II as a potential biomarker for the stratification of spondyloarthritis from rheumatoid arthritis.

OBJECTIVES: The discovery of diseased tissue-specific neoantigens offers the opportunity to develop important disease tissue-specific biomarkers that can help in the prediction, diagnosis, and stratification of diseases. This opportunity is specifically significant for autoimmune diseases where diagnostic biomarkers are not available. Inflammatory autoimmune diseases are commonly associated with local generation of large amounts of reactive oxidants. We have previously identified oxidative post-translationally modified (oxPTM) tissue-specific neoantigens in rheumatoid arthritis (RA) and type 1 diabetes that elicit an immune response. In the current study, we studied the presence and clinical significance of antibodies to oxPTM collagen type II (CII) in patients with spondyloarthritis (SpA). METHOD: Levels of antibodies specific to native CII and oxPTM-CII were assessed by enzyme-linked immunosorbent assay. RESULTS: Immunoglobulin G (IgG) binding to oxPTM-CII was observed in 52%, 83%, and 28% of serum samples from patients with axial spondyloarthritis (axSpA), RA, and psoriatic arthritis (PsA), respectively. Importantly, while strong IgA anti-oxPTM-CII responses were detected in axSpA and PsA patients, with 47% and 84% respective binders, no IgA anti-oxPTM-CII was detected in RA patients. IgA anti-oxPTM-CII reactivity in axSpA patients treated with biologics was higher and more frequent, with 85% binders compared to 9% binders in patients treated with synthetic disease-modifying anti-rheumatic drugs. CONCLUSION: Our data imply that SpA and PsA are associated with the presence of antibodies to oxPTM-CII, suggesting that there may be a humoral component that may distinguish patients with SpA from RA. Our approach could be adapted to other diseases, particularly to inflammatory autoimmune diseases.

Decrease in 14-3-3η protein levels is correlated with improvement in disease activity in patients with rheumatoid arthritis treated with Tofacitinib.

14-3-3η protein is a proinflammatory mediator that may represent a novel diagnostic and prognostic biomarker for rheumatoid arthritis (RA). We assessed the correlation between changes in serum 14-3-3η levels and changes in clinical disease activity measures in RA patients treated with Tofacitinib (TOF). Paired serum samples from 35 patients with RA were obtained at baseline and 5 months after the initiation of treatment with TOF. The levels of 14-3-3η were measured by JOINT stat 14-3-3η ELISA test kits (Augurex Life Sciences Corp.). The cut-off was defined as 0.19 ng/ml. 14-3-3η positivity was found in 57% of the patients at baseline and in 37% of the patients after 5 months of treatment. Mean ± SD baseline 14-3-3η levels [4.92 ± 8.86 ng/ml] were significantly higher (p < 0.005) than 14-3-3η levels following treatment [1.97 ± 4.59 ng/ml]. A statistically significant improvement (p < 0.001) of CDAI, SDAI, DAS4ESR and DAS4CRP was achieved after 5 month of treatment. Decrease in 14-3-3η protein levels was highly correlated with improvement in DAS4ESR (r = 0.50, p < 0.01), DAS4CRP (r = 0.46, p < 0.01) and ESR (r = 0.36, p = 0.03) and moderately correlated with improvement in CDAI (r = 0.32, p = 0.065) and SDAI (r = 0.33, p = 0.051). The correlation between decrease in 14-3-3η levels and improvement in DAS4ESR remained significant in a partial correlation analysis controlling for ESR (r = 0.39, p = 0.02). This study demonstrates that in RA patients who were treated with TOF, decrease in 14-3-3η levels is correlated with improvement in clinical disease activity parameters. The 14-3-3η protein may serve as an objective biomarker for monitoring of TOF therapy response.

Tuftsin-phosphorylcholine (TPC) equally effective to methylprednisolone in ameliorating lupus nephritis in a mice model.

The role of helminth treatment in autoimmune diseases is growing constantly. Systemic lupus erythematosus (SLE) is a multi-system autoimmune disease with challenging treatment options. Tuftsin-phosphorylcholine (TPC) is a novel helminth-based compound that modulates the host immune network. This study was conducted to evaluate the potential value of TPC in ameliorating lupus nephritis in a murine model and specifically to compare the efficacy of TPC to the existing first-line therapy for SLE: corticosteroids (methylprednisolone). Lupus-prone NZBxW/F1 mice were treated with TPC (5 µg/mouse), methylprednisolone (MP; 5 mg/body weight) or phosphate-buffered saline (PBS) (control) three times per week once glomerulonephritis, defined as proteinuria of grade > 100 mg/dl, was established. Levels of anti-dsDNA autoantibodies were evaluated by enzyme-linked immunosorbent assay (ELISA), splenic cytokines were measured in vitro and the kidney microscopy was analysed following staining. TPC and MP treatments improved lupus nephritis significantly and prolonged survival in NZBxW/F1 mice. TPC-treated mice showed a significantly decreased level of proteinuria (P < 0·001) and anti-dsDNA antibodies (P < 0·001) compared to PBS-treated mice. Moreover, TPC and MP inhibited the production of the proinflammatory cytokines interferon IFN-γ, interleukin IL-1ß and IL-6 (P < 0·001) and enhanced expression of the anti-inflammatory cytokine IL-10 (P < 0·001). Finally, microscopy analysis of the kidneys demonstrated that TPC-treated mice maintained normal structure equally to MP-treated mice. These data indicate that the small molecule named TPC hinders lupus development in genetically lupus-prone mice equally to methylprednisolone in most of the cases. Hence, TCP may be employed as a therapeutic potential for lupus nephritis.

Monitoring public interest toward pertussis outbreaks: an extensive Google Trends-based analysis.

OBJECTIVES: Pertussis is a vaccine-preventable disease. Despite this, it remains a major health problem among children in developing countries and in recent years, has re-emerged and has led to considerable outbreaks. Pertussis surveillance is of paramount importance; however, classical monitoring approaches are plagued by some shortcomings, such as considerable time delay and potential underestimation/underreporting of cases. STUDY DESIGN: This study aims at investigating the possibility of using Google Trends (GT) as an instrument for tracking pertussis outbreaks to see if infodemiology and infoveillance approaches could overcome the previously mentioned issues because they are based on real-time monitoring and tracking of web-related activities. METHODS: In the present study, GT was mined from inception (01 January 2004) to 31 December 2015 in the different European countries. Pertussis was searched using the 'search topic' strategy. Pertussis-related GT figures were correlated with the number of pertussis cases and deaths retrieved from the European Centre for Disease prevention and Control database. RESULTS: At the European countries level, correlation between pertussis cases and GT-based search volumes was very large (ranging from 0.94 to 0.97) from 2004 to 2015. When examining each country, however, only a few reached the threshold of statistical significance. CONCLUSIONS: GT could be particularly useful in pertussis surveillance and control, provided that the algorithm is better adjusted and refined at the country level.

Intravenous immunoglobulin: a biological corticosteroid-sparing agent in some autoimmune conditions.

Intravenous immunoglobulin (IVIg) is increasingly used for the treatment of autoimmune and systemic inflammatory diseases. This compound is effective in a wide range of clinical conditions other than primary immunodeficiency, including autoimmune diseases, inflammatory disorders, infections, organ transplantation, and possibly supportive therapy for cancer. Systemic corticosteroids remain the gold standard treatment for many autoimmune diseases, but their long-term use is associated with complications in diverse organs and systems. Osteoporosis, osteonecrosis, cardiovascular disease, infections, and cancer have been associated with this treatment. Therefore, physicians are occasionally forced to withdraw the treatment with steroids. Biological agents may represent a good alternative, but in addition to being very expensive, these agents may have serious side effects. This review aimed to cover the major advances in the use of IVIg as a steroid-sparing agent in some relevant autoimmune diseases.

Anterior ST-elevation myocardial infarction induced by rituximab infusion: A case report and review of the literature.

WHAT IS KNOWN AND OBJECTIVES: Rituximab is a chimeric monoclonal anti-CD20 antibody approved for the treatment of some lymphoid malignancies as well as for autoimmune diseases including rheumatoid arthritis (RA), idiopathic thrombocytopenic purpura (ITP) and vasculitis. Generally, rituximab is well tolerated; nevertheless, some patients develop adverse effects including infusion reactions. Albeit rare, these reactions may in some cases be life-threatening conditions. Rituximab cardiovascular side effects include more common effects such as hypertension, oedema and rare cases of arrhythmias and myocardial infarction. CASE SUMMARY: In this article, we report a case of a 58-year-old man with a history of overlap syndrome including RA and limited scleroderma who was treated with rituximab and developed a dramatic ST-elevation myocardial infarction (STEMI) during the drug administration. WHAT IS NEW AND CONCLUSION: This report underlines previous published reports emphasizing the awareness of such an association. This communication also warrants the importance of screening for ischaemic heart disease in selected cases of patients treated with rituximab.

Aortic aneurysm association with SLE - a case-control study.

OBJECTIVES: Aortic aneurysm is a life threatening cardiovascular complication in patients with systemic lupus erythematosus (SLE).The purpose of this study was to investigate the association between SLE and occurrence of aortic aneurysms. METHODS: Patients with SLE were compared with age- and sex-matched controls regarding the proportion of aortic aneurysm in a case-control study. Chi-square and t-tests were used for univariate analysis and a logistic regression model was used for multivariate analysis. The study was performed utilizing the medical database of Clalit Health Services. RESULTS: The study included 5018 patients with SLE and 25,090 age- and sex-matched controls. The proportion of aortic aneurysm in patients with SLE was increased compared with the proportion in controls (0.6% and 0.1%, respectively, p < 0.001). In a multivariate analysis SLE was associated with the coexistence of aortic aneurysms (odds ratio 2.06, 95% confidence interval 1.21-3.51). CONCLUSIONS: Patients with SLE have a higher proportion of aortic aneurysms as compared with matched controls. Therefore, physicians treating patients with SLE should be aware of this life threatening association.

A randomised, double-blinded study comparing giving etoricoxib vs. placebo to female patients with fibromyalgia.

OBJECTIVES: Current therapeutic approaches to fibromyalgia syndrome (FMS) do not provide satisfactory pain control to a high percentage of patients. This unmet need constantly fuels the pursuit for new modalities for pain relief. This randomised, double-blind, controlled study assessed the efficacy and safety of adding etoricoxib vs. placebo to the current therapeutic regimen of female patients with FMS. METHODS: In this double-blind, placebo-controlled study, female patients were randomised to receive either 90 mg etoricoxib once daily or placebo for 6 weeks. Several physical and mental parameters were assessed throughout the study. The primary end-point was the response to treatment, defined as ≥ 30% reduction in the average Brief Pain Inventory score. Secondary outcomes were changes in the Fibromyalgia Impact Questionnaire, SF-36 Quality of Life assessment questionnaire and Hamilton rating scales for anxiety and depression. RESULTS: Overall, 73 patients were recruited. Although many outcome measures improved throughout the study, no difference was recorded between the etoricoxib- and placebo-treated groups. The Brief Pain Inventory, Fibromyalgia Impact Questionnaire, The Hamilton Anxiety and Depression scores did not differ between the two groups. CONCLUSIONS: This is the first randomised, double-blind study assessing the effect of adding etoricoxib to pre-existing medications for female patients with FMS. Although being mildly underpowered this study clearly has shown that etoricoxib did not improve pain scores and did not lead to any beneficial mental or physical effects.

Anti-citrullinated-protein-antibody-specific intravenous immunoglobulin attenuates collagen-induced arthritis in mice.

Administration of intravenous immunoglobulin (IVIg) is a recognized safe and efficient immunomodulation therapy for many autoimmune diseases. Anti-idiotypic antibody binding to pathogenic autoantibodies was proposed as one of the mechanisms attributed to the protective activity of IVIg in autoimmunity. The aim of this study was to fractionate the anti-anti-citrullinated protein anti-idiotypic-antibodies (anti-ACPA) from an IVIg preparation and to test it as a treatment for collagen-induced arthritis in mice. IVIg was loaded onto an ACPA column. The eluted fraction was defined as ACPA-specific-IVIg (ACPA-sIVIg). Collagen-induced-arthritis (CIA) was induced in mice. Mice were treated weekly with ACPA-sIVIg, low-dose-IVIg, high-dose-IVIg and phosphate-buffered saline (PBS). Sera-ACPA titres, anti-collagen anitbodies and cytokine levels were analysed by enzyme-linked immunosorbent assay (ELISA); antibody-forming-cell activity by enzyme-linked imunospot (ELISPOT) assay; and expansion of regulatory T cell (Treg ) population by fluorescence activated cell sorter (FACS). ACPA-sIVIg inhibited ACPA binding to citrullinated-peptides (CCP) in vitro 100 times more efficiently than the IVIg compound. ACPA-sIVIg was significantly more effective than the IVIg-preparation in attenuating the development of collagen-induced arthritis. Splenocytes from CIA mice treated with ACPA-sIVIg reduced the ACPA and anti-collagen-antibody titres, including the number of anti-collagen and ACPA antibody-forming cells. In parallel, splenocytes from ACPA-sIVIg treated mice secreted higher levels of anti-inflammatory cytokines and lower proinflammatory cytokines. The ACPA-sIVIg inhibitory potential was accompanied with expansion of the Treg population. Low-dose IVIg did not affect the humoral and cellular response in the CIA mice in comparison to the PBS-treated mice. Based on our results, IVIg may be considered as a safe compound for treating patients with rheumatoid arthritis by neutralizing pathogenic autoantibodies, reducing proinflammatory cytokines and expanding the Treg population.

Adherence to statins and the risk of psoriasis: a population-based cohort study.

BACKGROUND: Statins have been shown to downregulate immune mechanisms activated in psoriasis. However, previous studies on their potential role in preventing psoriasis have yielded conflicting results. OBJECTIVES: To assess the relationship between adherence to statins and the risk of psoriasis. METHODS: This retrospective cohort study included 205,820 health plan enrollees in Israel (mean age 55 years; 54·1% women) who initiated statin treatment from January 1998 through to September 2009. Adherence to statins, measured by the proportion of days covered (PDC), throughout the entire follow-up period (mean 6·2 years) was recorded. Diagnosis codes of psoriasis were assigned by a dermatologist or rheumatologist, or at discharge from hospital. RESULTS: During 1·28 million person-years (PY) of follow-up (median 5·74 years per person; interquartile range 3·78-8·36), 5615 cases of psoriasis (incidence density rate 4·4 per 1000 PY) were recorded. Compared with patients who did not adhere to statins (PDC < 20%), patients covered by statins for 40-59% of the time had a significantly lower risk of psoriasis (P < 0·05), with hazard ratios (HRs) of 0·84 and 0·74 among men and women, respectively. Among patients who adhered better to statins (PDC ≥ 80%), HRs were 0·88 (95% CI 0·79-0·98) and 1·00 (95% CI 0·90-1·11) among men and women, respectively. CONCLUSIONS: The results of the current study suggest that high and long-term adherence to statins is not associated with a meaningful reduction in the risk of developing psoriasis.

A randomized double-blind placebo-controlled study adding high dose vitamin D to analgesic regimens in patients with musculoskeletal pain.

BACKGROUND: The current mode of therapy for many patients with musculoskeletal pain is unsatisfactory. PURPOSE: We aimed to assess the impact of adding 4000 IU of vitamin D on pain and serological parameters in patients with musculoskeletal pain. MATERIALS AND METHODS: This was a randomized, double-blinded and placebo-controlled study assessing the effect of 4000 IU of orally given vitamin D3 (cholecalciferol) (four gel capsules of 1000 IU, (SupHerb, Israel) vs. placebo on different parameters of pain. Eighty patients were enrolled and therapy was given for 3 months. Parameters were scored at three time points: prior to intervention, at week 6 and week 12. Visual analogue scale (VAS) scores of pain perception were recorded following 6 and 12 weeks. We also measured serum levels of leukotriene B4 (LTB4), interleukin 6 (IL-6), tumor necrosis factor alpha (TNFα) and prostaglandin E2 (PGE2) by ELISA. RESULTS: The group receiving vitamin D achieved a statistically significant larger decline of their VAS measurement throughout the study compared with the placebo group. The need for analgesic 'rescue therapy' was significantly lower among the vitamin D-treated group. TNFα levels decreased by 54.3% in the group treated with vitamin D and increased by 16.1% in the placebo group. PGE2 decreased by39.2% in the group treated with vitamin D and increased by 16% in the placebo group. LTB4 levels decreased in both groups by 24% (p < 0.05). CONCLUSION: Adding 4000 IU of vitamin D for patients with musculoskeletal pain may lead to a faster decline of consecutive VAS scores and to a decrease in the levels of inflammatory and pain-related cytokines.

Vitamin D: an instrumental factor in the anti-phospholipid syndrome by inhibition of tissue factor expression.

BACKGROUND AND AIMS: Antiphospholipid syndrome (APS) is a systemic autoimmune disease characterised by thrombosis, obstetric complications and the presence of anti-phospholipid antibodies such as anti-ß2GPI-Abs. These antibodies may set off the coagulation cascade via several mechanisms, including the induction of tissue factor (TF) expression. Vitamin D has recently emerged as an immunomodulator that might exert an anti-thrombotic effect. Therefore, we studied serum vitamin D levels in a cohort of APS patients, as well as the effect of vitamin D in an in vitro model of APS-mediated thrombosis. METHODS: Serum vitamin D levels were measured in 179 European APS patients and 141 healthy controls using the LIAISON chemiluminescent immunoassay, and the levels were evaluated in conjunction with a wide spectrum of clinical manifestations. In an vitro model, anti-ß2GPI antibodies were purified from four patients with APS to evaluate the expression of TF in activated starved human umbilical vein endothelial cells. The effect of vitamin D (1,25-dihydroxyvitamin D, 10 nm) on anti-ß2GPI-Abs mediated TF expression was analysed by immunoblot. RESULTS: Vitamin D deficiency (serum level ≤15 ng/ml) was documented in 49.5% of our APS patients versus 30% of controls (p<0.001) and was significantly correlated with thrombosis (58% vs 42%; p<0.05), neurological and ophthalmic manifestations, pulmonary hypertension, livedo reticularis and skin ulcerations. In vitro vitamin D inhibited the expression of TF induced by anti-ß2GPI-antibodies. CONCLUSIONS: Vitamin D deficiency is common among APS patients and is associated with clinically defined thrombotic events. Vitamin D inhibits anti-ß2GPI-mediated TF expression in vitro. Thus, vitamin D deficiency might be associated with decreased inhibition of TF expression and increased coagulation in APS. Evaluation of vitamin D status and vitamin D supplementation in APS patients should be considered.

Higher rates of COVID-19 but less severe infections reported for patients on Dupilumab: a Big Data analysis of the World Health Organization VigiBase.

OBJECTIVE: Dupilumab (Dupixent®) is a monoclonal antibody that inhibits IL-4 and IL-13 signaling used for the treatment of allergic diseases. Whilst biologic therapy is traditionally regarded as immunosuppressive and capable to increase the infectious risk, Dupilumab does not display these characteristics and may be even protective in certain cases. We investigated the link between Dupilumab therapy and SARS-CoV-2 infection. MATERIALS AND METHODS: We carried out a comprehensive data mining and disproportionality analysis of the WHO global pharmacovigilance database. One asymptomatic COVID-19 case, 106 cases of symptomatic COVID-19, and 2 cases of severe COVID-19 pneumonia were found. RESULTS: Dupilumab treated patients were at higher risk of COVID-19 (with an IC0.25 of 3.05), even though infections were less severe (IC0.25 of -1.71). The risk of developing COVID-19 was significant both among males and females (with an IC0.25 of 0.24 and 0.58, respectively). The risk of developing COVID-19 was significant in the age-group of 45-64 years (with an IC0.25 of 0.17). CONCLUSIONS: Dupilumab use seems to reduce COVID-19 related severity. Further studies are needed to better understand the immunological mechanisms and clinical implications of these findings. Remarkably, the heterogenous nature of the reports and the database structure did not allow to establish a cause-effect link, but only an epidemiologically decreased risk in the patients subset treated with dupilumab.

Serum concentrations of 25-OH vitamin D in patients with systemic lupus erythematosus (SLE) are inversely related to disease activity: is it time to routinely supplement patients with SLE with vitamin D?

BACKGROUND: Low serum vitamin D concentrations have been reported in several autoimmune disorders. OBJECTIVE: To assess whether low serum vitamin D concentrations are related to disease activity of patients with systemic lupus erythematosus (SLE). METHODS: 378 patients from several European and Israeli cohorts were pooled and their disease activity was measured by two different methods: 278 patients had SLE disease activity-2000 (SLEDAI-2K) scores and 100 patients had European Consensus Lupus Activity Measurement (ECLAM) scores. In order to combine the two systems the scores were converted into standardised values (z-scores), enabling univariate summary statistics for the two variables (SLEDAI-2K and ECLAM). The commercial kit, LIAISON 25-OH vitamin D assay (310900-Diasorin) was used to measure serum concentration of 25-OH vitamin D in 378 patients with SLE. RESULTS: A significant negative correlation was demonstrated between the serum concentration of vitamin D and the standardised values (z-scores) of disease activity scores as measured by the SLEDAI-2K and ECLAM scales (Pearson's correlation coefficient r=-0.12, p=0.018). CONCLUSIONS: In a cohort of patients with SLE originating from Israel and Europe vitamin D serum concentrations were found to be inversely related to disease activity.

The anti-inflammatory target A(3) adenosine receptor is over-expressed in rheumatoid arthritis, psoriasis and Crohn's disease.

The Gi protein associated A(3) adenosine receptor (A(3)AR) was recently defined as a novel anti-inflammatory target. The aim of this study was to look at A(3)AR expression levels in peripheral blood mononuclear cells (PBMCs) of patients with autoimmune inflammatory diseases and to explore transcription factors involved receptor expression. Over-expression of A(3)AR was found in PBMCs derived from patients with rheumatoid arthritis (RA), psoriasis and Crohn's disease compared with PBMCs from healthy subjects. Bioinformatics analysis demonstrated the presence of DNA binding sites for nuclear factor-kappaB (NF-kappaB) and cyclic AMP-responsive element binding protein (CREB) in the A(3)AR gene promoter. Up-regulation of NF-kappaB and CREB was found in the PBMCs from patients with RA, psoriasis and Crohn's disease. The PI3K-PKB/Akt signaling pathway, known to regulate both the NF-kappaB and CREB, was also up-regulated in the patients' PBMCs. Taken together, NF-kappaB and CREB are involved with the over-expression of A(3)AR in patients with autoimmune inflammatory diseases. The receptor may be considered as a specific target to combat inflammation.

Gender differences in cardiovascular risk of patients with rheumatoid arthritis.

BACKGROUND: Rheumatoid Arthritis (RA) is a chronic inflammatory disease, affecting women more than men, with a more aggressive course in women. DESIGN: A prospective study that recruited 58 patients (46 women aged 56 ± 12 years) with active long-standing RA disease (>12 months). Our goals were to measure their endothelial function, part of the cardiovascular risk assessment. METHODS: The Brachial Artery method measured endothelial function (the flow mediated percent change [FMD percentage] of the brachial artery diameter). A senior Rheumatologist clinically evaluated all subjects. Mann Whitney rank sum test estimated gender differences among the RA patients. RESULTS: Median FMD% change for men was -6.07%, while median FMD% change for women was 0.44% (Z = 2.38, P = 0.01). Baseline Brachial artery diameter was larger in men (Z = 2.52, P = 0.01); however, tender joints count and BMI were greater in women (Z=-2.24, P = 0.01; Z=-3.99, P = 0.001), respectively. CONCLUSIONS: Women with RA have significantly better endothelial function than men with RA. It means that even though RA is 3-fold more prevalent in women, women are more protected from atherosclerotic coronary artery disease and cardiac events.