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Objectives The effectiveness of the BNT162b2 mRNA COVID-19 vaccine for adolescents with juvenile-onset inflammatory or immune rheumatic diseases (IRDs) is unknown. Several studies have suggested attenuated immunogenicity in patients with IRD. This study evaluated the effectiveness of the BNT162b2 mRNA COVID-19 vaccine in preventing COVID-19 infection in adolescents with juvenile-onset IRD compared with controls without immune rheumatic disease. Methods We used data from Clalit Health Services, the largest health-care organization in Israel, to conduct an observational cohort study from February to December 2021, involving 12–18 year-old adolescents diagnosed with IRD. Study outcomes included documented COVID-19 infection in relation to vaccination status and immunomodulatory therapy. We estimated vaccine effectiveness as one minus the risk ratio. Adolescents aged 12–18 years without immune rheumatic disease served as controls. Results A total of 1639 adolescents with IRD (juvenile idiopathic arthritis, SLE, or familial Mediterranean fever) were included and compared with 524 471 adolescents in the same age range without IRD. There was no difference in COVID-19 infection rates after the second dose of vaccine between those with IRD and controls (2.1% vs 2.1% respectively, P = 0.99). The estimated vaccine effectiveness for adolescents with IRD was 76.3% after the first dose, 94.8% after the second and 99.2% after the third dose. Conclusion We found that the BNT162b2 mRNA vaccine was similarly effective against COVID-19 infection in adolescents with and without IRD. Immunomodulatory therapy did not affect its effectiveness. These results can encourage adolescents with IRD to get vaccinated against COVID-19.

Aims This study evaluated the impact of serum uric acid (sUA) on the accuracy of pooled cohort equations (PCE) model, Systematic COronary Risk Evaluation 2 (SCORE2), and SCORE2-older persons. Methods and results We evaluated 19 769 asymptomatic self-referred adults aged 40–79 years free of cardiovascular disease and diabetes who were screened annually in a preventive healthcare setting. sUA levels were expressed as a continuous as well as a dichotomous variable (upper sex-specific tertiles defined as high sUA). The primary endpoint was the composite of death, acute coronary syndrome, or stroke, after excluding subjects diagnosed with metastatic cancer during follow-up. Mean age was 50 ± 8 years and 69% were men. During the median follow-up of 6 years, 1658 (8%) subjects reached the study endpoint. PCE, SCORE2, and high sUA were independently associated with the study endpoint in a multivariable model (P < 0.001 for all). Continuous net reclassification improvement analysis showed a 13% improvement in the accuracy of classification when high sUA was added to either PCE or SCORE2 model (P < 0.001 for both). sUA remained independently associated with the study endpoint among normal-weight subjects in the SCORE2 model (HR 1.3, 95% CI 1.1–1.6) but not among overweight individuals (P for interaction = 0.01). Subgroup analysis resulted in a significant 16–20% improvement in the model performance among normal-weight and low-risk subjects (P < 0.001 for PCE; P = 0.026 and P < 0.001 for SCORE2, respectively). Conclusion sUA significantly improves the classification accuracy of PCE and SCORE2 models. This effect is especially pronounced among normal-weight and low-risk subjects.

INTRODUCTION Inflammatory myopathies are treated with glucocorticoids and other immunosuppressive medications. Intravenous immunoglobulin (IVIG) is increasingly used for refractory or severe cases; however, the evidence for their effectiveness is limited. We assessed effectiveness and safety of IVIG when used with other immunomodulatory agents in the treatment of inflammatory myopathies. METHODS This study reviewed records of patients diagnosed with dermatomyositis or polymyositis and treated with IVIG, from 2009 through 2016 in 1 tertiary medical center. Mixed-effects general linear regression models were applied to determine effectiveness of treatment on muscle strength, creatinine phosphokinase levels, and steroid dosage. RESULTS Twenty-three patients with dermatomyositis/polymyositis treated with IVIG were followed up for a mean of 31 (SD, ±25) months. During this period, a significant improvement in muscle strength was demonstrated, with a mean increase of 0.92 Medical Research Council scale points (β = 0.14; confidence interval [CI], 0.136-0.149; p < 0.0001), a significant reduction of creatinine phosphokinase levels and steroid dosage with a mean decrease of 1140 IU/L (β = -0.274; CI, -0.354 to -0.195; p < 0.0001), and 36 mg/d (β = -0.008; CI, -0.011 to -0.006; p < 0.0001), respectively. Overall, remission was observed in 10 patients (43.5%), and partial remission in 6 patients (26%), whereas 1 patient (17%) remained refractory to treatment, and 6 patients (27%) were lost to follow-up. CONCLUSIONS The majority of patients with inflammatory myopathies experienced a clinical and laboratory improvement during IVIG treatment. In addition, a steroid-sparing effect was noticed in most patients. These results encourage the use of IVIG as an alternative treatment option for patients with limited responsiveness to conventional methods.

The COVID-19 outbreak has led to the rapid development and administration of the COVID-19 vaccines worldwide. Data about the immunogenicity and adverse effects of the vaccine on patients with systemic autoimmune rheumatic diseases (SARDs) is emerging.To evaluate Pfizer/BioNTech (BNT162b2) mRNA-based vaccine second-dose immunogenicity and safety, and the relation between them, in patients with SARDs.A total of one hundred forty tow adults who received two doses of the BNT162b2 vaccine were included in the study. The SARDs group included Ninety-nine patients and the control group (forty-three participants) comprised a mixture of healthy participants and patients who were seen at the rheumatology clinic for non-SARDs. Anti-SARS-CoV-2 IgG antibodies against the Spike protein were evaluated using a SARS-CoV-2 IgG immunoassay. A level of 150 AU/mL was considered positive. An adverse effects questionnaire was given to the participants upon their first visit to the clinic after their BNT162b2 vaccination.Of the 142 participants, 116 were seropositive (81.7%) and 26 (18.3%) were seronegative. Of the seronegative participants, 96.2% were SARDs patients. The proportion of seropositivity in the SARDs patients treated with any immunosuppressant was significantly lower (69.9%) compared to the control group and SARDs patients not receiving immunosuppressants (96.8%). A significant negative correlation between seronegativity and treatment with rituximab, mycophenolate mofetil (MMF), and prednisone was found in the SARDs group (p = 0.004, 0.044, 0.007 respectively). No fever was observed following the BNT162b2 vaccine in seronegative patients, and the frequency of musculoskeletal adverse effects upon the second dose of the BNT162b2 vaccine was significantly higher in seropositive compared to seronegative patients and in the control group compared to the SARDs patients (p = 0.045, p = 0.02 respectively).A decline in the immunogenicity to the second dose of BNT162b2 mRNA is seen in patients with SARDs, especially in patients treated with rituximab, MMF, and prednisone. Adverse effects of the vaccine including fever and musculoskeletal symptoms might be a signal for the acquisition of immunity in those patients.• BNT162b2 mRNA vaccine is less immunogenic in SARDs patients compared to the control group. • Rituximab, prednisone, and mycophenolate mofetil significantly reduced immunogenicity to the vaccine. • There is a correlation between immunogenicity and adverse effects of the vaccine.

Clinically amyopathic dermatomyositis is an uncommon autoimmune disorder in the Middle East. The clinical picture of clinically amyopathic dermatomyositis is characterized mainly by pulmonary and dermatological manifestations. Occasionally muscle symptoms are observed as well. Serum anti-MDA5 autoantibody positivity is associated with rapidly progressive interstitial lung disease among clinically amyopathic dermatomyositis patients. Moreover, high serum ferritin level is correlated with poor prognosis and high mortality. Herein we describe the case of an Israeli patient with rapidly progressive interstitial lung disease and without pathognomonic dermatological features who was diagnosed with anti-MDA5 positive clinically amyopathic dermatomyositis and did not survive despite immunomodulatory therapy followed by reduction in serum ferritin levels.

Background Paraneoplastic neurological syndromes (PNS) are a group of syndromes that affect the central and peripheral neuromuscular system in association with cancer. Specific antibodies may assist in the diagnosis of PNS. The antibodies tested can be classified into those directed against intracellular neuronal proteins (“well characterized” PNS: Hu, Yo, RI, CV2, amphiphysin, Ma1, Ma2) and those directed against neural surface antigens (autoimmune encephalitis syndromes: NMDA, AMPA, LGI1, CASPR2, GABAR). We aimed to characterize patients with unexplained neuropsychiatric symptoms, in whom positive PNS antibodies were detected in the Sheba medical center, a large referral hospital. Methods Clinical and demographic data of patients with positive PNS antibodies were collected during the years 2002–2016. Antibodies were tested by either Line immunoassay or by cell-based indirect immunofluorscent assay. Results During the follow up of 14 years, 4010 PNS tests were performed in patients with unexplained neuropsychiatric symptoms. Seventy-two were found to be positive; among them we had full clinical data access to 44. The most frequent antibodies were anti-Hu (31.8%), anti-Yo (18.2%), anti-CV2 (13.6%), and anti-NMDA (9.1%), and the most common cancers were small-cell lung (SCLC) and ovarian cancers. In the well characterized paraneoplastic group, cancer was diagnosed in 55.9% of the patients, and in the autoimmune encephalitis group, 40.0% were diagnosed with cancer. A positive correlation between antibody titer and the presence of cancer was found. Ninety percent of the tests in patients who were found positive were ordered by a neurologist or neuro-oncologist. Conclusions The titers of PNS auto-antibodies can predict cancer in patients whom anti-PNS antibodies are tested. In addition, consultation with a specialist should be considered before this test is ordered.

Clinical and experimental data support a critical role for inflammation in cardiovascular disease. The purpose of the current study was to examine the relation between an inflammatory marker, neutrophil-to-lymphocyte ratio (NLR), and incident atrial fibrillation (AF) in asymptomatic adults. We investigated 21,118 self-referred men and women who were annually screened in a tertiary medical center. All subjects were free of AF at baseline and had their serum NLR calculated at the first annual visit. Subjects were divided into 2 groups based on their baseline NLR: Low (2.83; n = 17,524) and high (≥2.83; n = 3,594; Upper Sextile). The primary endpoint was new onset AF during follow-up. Mean age of study population was 48 ± 10 years and 72% were men. A total of 563 (2.7%) incident events occurred during an average follow-up of 7.5 ± 5 years. Unadjusted Cox regression analysis demonstrated that each 1 unit increase in NLR was associated with a significant 14% increase in risk of occurrence of a first AF event (95% confidence interval 1.06 to 1.23, p0.001) and 20% increased risk of death. Kaplan-Meier's survival analysis showed that the cumulative probability of incident AF was significantly higher among subjects with high NLR compared with low NLR group (p = 0.006). Interaction analysis with adjustment to clinical parameters showed that NLR-related risk was age-dependent, such that in the younger age-group (=50 years) high NLR group had two folds increased risk for AF event compared with low NLR group (95% confidence interval 1.08 to 3.51; p = 0.027) whereas among older subjects the rate of events was similar between both NLR groups (p = NS; p for interaction = 0.024). In conclusion, our findings suggest that high NLR is associated with increased risk of new onset AF. This finding is more pronounced among young adults.

To evaluate the association between inflammatory back pain (IBP) features, acute and structural MRI findings suggestive of sacroiliitis, and diagnosis of spondyloarthritis (SpA). Data from 224 patients who underwent MRI for suspected sacroiliitis (2005–2015) was retrospectively reviewed by an expert rheumatologist for the presence of IBP features and for clinical standard of reference diagnosis. A telephone questionnaire was performed in cases of missing data. Acute and structural MRI parameters were scored by an experienced radiologist for the presence of sacroiliitis using the Assessment of Spondyloarthritis International Society (ASAS) criteria, Berlin score, and observer’s global impression (GI) scores. Association between IBP features and MRI scores, and odds ratio for SpA diagnosis, were calculated. One hundred ninety-three subjects were included (119 F:74 M, mean age 39.7 ± 15.6, mean follow-up 49 ± 18 months). Fifty-two (26.9%) subjects were diagnosed with SpA. IBP scores were significantly higher in SpA patients (p

Objective FMF is an autoinflammatory disease of genetic origin. Colchicine is the mainstay of treatment for the prevention of attacks and long-term complications but 5–10% of FMF patients are resistant to colchicine therapy. The aim of our study was to investigate the real-life safety and efficacy of anakinra in a cohort of patients with colchicine-resistant FMF. Methods In this retrospective study, patients treated with anakinra for colchicine-resistant FMF between 2010 and 2018 were identified using the computerized database of Sheba Medical Center and enrolled in the study. Data from structured clinical files were analysed to evaluate the efficacy and safety outcomes. To assess efficacy, we used the Global Assessment Score (GAS), a measure comprised of three different domains: number of attacks per month, duration of attacks and number of sites involved in the attacks. Reported adverse events were compiled. Results A total of 44 patients (24 female) were treated with anakinra. Of these patients, 75% were homozygous for the M649V mutation. The mean duration of treatment was 18 months. The GAS decreased significantly from 6.6 (IQR 5.3–7.8) before treatment to 2 (IQR 0–4.2) while on treatment (P Conclusion Treatment with anakinra is beneficial for the majority of colchicine-resistant FMF patients and is relatively safe.

Background SLE complexity and unpredictability challenge assessment of disease activity. Current scoring instruments are limited in ability to detect changes in activity over time and too cumbersome for daily practice. We constructed a new disease activity score, including physician and patient assessment, aiming to simplify and improve assessment in daily practice, and possibly serve as a tool for clinical studies. Methods The new instrument is comprised of 6 visual analogue scales, separately addressing the physician’s global assessment and 5 organ systems: mucocutaneous, musculoskeletal, cardiorespiratory, renal and neuropsychiatric systems, and 5 visual analogue scales addressing patients’ assessment of disease activity and adherence to therapy. Laboratory values and medications are recorded. Aiming to assess the reliability and validity of the new score, as well as it’s sensitivity to changes in disease activity, 4 paper cases, including 2 visits per case, were constructed. Each visit was scored by 5 experienced rheumatologists, using BILAG, SLEDAI, LFA-REAL and our proposed score. Results The inter-rater reliability of the new score was good for all systems, both for single visit scores and for change in disease activity between 2 consecutive visits (ICC [2,1] range 0.75–0.95), except for changes in activity in the renal system (0.59). The inter-rater reliability values of the new score were comparable with those of the BILAG and the LFA-REAL instruments. The construct validity of the new score was good for single visit scores (Spearman correlation coefficients range 0.48–0.94). Correlation of our proposed score with the BILAG, was good when scoring the mucocutaneous, musculoskeletal and cardiorespiratory systems (0.66, 0.75, 0.83, respectively) but poor when scoring the renal system (0.11). Conclusions This paper case evaluation of the new disease activity score suggests a promising and simple tool, with overall good reliability and construct validity.

BACKGROUND Data on the association between AF and fitness are conflicting. OBJECTIVES The aim of this analysis was to investigate the association between fitness, obesity and incidence of atrial fibrillation (AF) among apparently healthy non-athlete adults. METHODS We investigated 20 410 self-referred subjects who were annually screened in a tertiary medical centre. All subjects were free of AF and completed maximal exercise stress test according to the Bruce protocol at baseline. Fitness was categorised into age- and sex-specific quintiles (Q) according to the treadmill time. Subjects were categorised to low (Q1-Q2) and high fitness (Q3-5) groups. The primary end point was new-onset AF during follow-up. RESULTS Mean age was 48 ± 10 years and 72% were men. A total of 463 (2.3%) events occurred during an average follow-up of 8 ± 5 years corresponding to an AF event rate of 0.3% per person year. Univariate and multivariate models showed that AF risk was similar in both fitness groups. However, AF event rate was 0.55% per person year among high fitness obese subjects, compared with 0.31% for low fitness obese subjects (P

Inflammatory myopathies are a clinically diverse group of diseases, in which the detection of particular autoantibodies may facilitate diagnosis, treatment, and prognosis. The aim of this report is to summarize our experience with specific autoantibody testing in patients with inflammatory myopathies. Data were collected over the last decade in the Autoimmune Center of the Sheba Medical Center, a tertiary referral hospital. Data regarding patients' positive for autoantibodies against Jo-1, PL-7, PL-12, SRP, Mi-2, Ku, and PM-Scl antigens were retrospectively collected. Patient demographics, clinical characteristics, and mortality were recorded. Descriptive statistics (mean, standard deviation, frequency, and percentage) were calculated. A total of 507 patients were surveyed for sclero-poly-synthetase antibodies, as part of the diagnostic workup of myositis/myalgia or interstitial lung disease. Forty-three patients were found positive for one or more of the abovementioned antibodies, and 23 of them (53.49%) had interstitial lung disease (ILD). Four patients were positive for anti-PL-7, three of them had ILD and Raynaud's phenomenon. Five patients were positive for anti-Ku, and four of them had both arthritis and Raynaud's phenomenon. Nine patients were positive for anti-Mi-2, and six of them were given diagnosed with dermatomyositis. Ten patients were positive for anti-SRP, and six of them had cancers of various types. Our results reiterate the previously recognized associations between anti-Mi-2 and dermatomyositis, anti-Ku and Raynaud's phenomenon, and between anti-PL-7 and ILD. In addition, our data support an association between anti-SRP autoantibody positivity and malignancy, which calls for further investigation.

Sjogren's syndrome is associated with chronic cough, but sicca symptoms are missing from cough evaluation guidelines. We evaluated patients with unexplained cough for undiagnosed Sjogren's syndrome. Patients referred to our pulmonary clinic (Sheba Medical Center, 2009 to 2012) with unexplained cough and concomitant dry eyes were selected for evaluation. Unexplained cough was defined as chronic cough of unknown etiology despite algorithm-based evaluation and treatment. Patients were evaluated in a dedicated clinic by a pulmonologist, rheumatologist, and ophthalmologist specializing in autoimmune disease. Patients completed the Leicester Cough Questionnaire, spirometry, antibody testing for anti Ro/La, ophthalmologic examination with visual acuity, eyelid, ocular surface fluorescein staining, tear break-up time and Schirmer's test, full slit lamp, and fundus examinations. Four-year follow-up was conducted by telephone questionnaire. We identified 24 patients among which 22 (21 females) agreed for evaluation. Eight patients (36%), seven initially, and one during follow-up were diagnosed with Sjogren's syndrome (SS) (six secondary and two primary SS). At 4-year follow-up, cough tended to persist and improve in only 37% with SS. These include 2 (Scl and RA) who received rituximab and 1 (stage 1 sarcoidosis) with spontaneous improvement. In contrast, cough improved in most (64%) patients without SS; the majority (eight/nine) report intensified disease-specific treatment (five allergic and three GERD). We describe patients in whom unexplained chronic cough was associated with dry eyes. Focused workup revealed undiagnosed Sjogren's syndrome in 36%. Dry eyes, with or without SS, is under-recognized and should be added to diagnostic algorithms for unexplained cough.

Objective Familial Mediterranean fever (FMF) is an autoinflammatory disease manifested with recurrent serosal inflammation. The association between FMF and malignancy has not been described. The aim of this study was to estimate cancer risk in a large single-institution cohort of FMF patients. Methods The study cohort consisted of 8,534 FMF patients registered in the Israel National FMF Center at Tel Hashomer, Israel. We linked the study cohort to the database of the Israel National Cancer Registry using the national identity number. Cancer incidence in FMF patients was determined and stratified by age and gender. Standardized incidence ratios (SIR) for cancers were calculated. Results Among 8,534 FMF patients (4,400 men, 4,134 women), 350 developed cancer during the years 1970-2011. Overall cancer risk among patients with FMF was significantly lower than that expected in the following gender and ethnic groups of the Israeli population: males of Jewish ethnicity SIR 0.66, CI 95% [0.55-0.77], p

Background Intravenous immunoglobulins (IVIG) are a biologic product originally developed to treat immunocompromised patients. In the past decades, there has been increased utilization of IVIG in autoimmune conditions. The objectives were to evaluate the clinical use of IVIG in the largest tertiary medical center in Israel and to determine top uses, estimate off-label usage, and assess consumption of this blood product. Study design and methods We conducted an observational, retrospective study involving all patients who received IVIG from 2007 through 2015. Subjects were classified into five groups according to the indication for treatment. Results A total of 1117 patients were identified. The mean (±SD) ages of adults and children were 55 ± 17 and 8 ± 7 years, respectively. Most common indication for treatment were immune-mediated conditions (54%), followed by secondary immunodeficiency (28%), primary immunodeficiency (10%), infections (4%), and miscellaneous (4%). The main immune-mediated conditions treated were hematologic disorders (305 patients, 27%), neurologic disorders (219 patients, 20%), and rheumatologic conditions (79 patients, 7%). Overall, a significant change in study period was observed in the number of patients (p Conclusion In this study, we demonstrated that immune-mediated conditions represent the majority of indications for treatment with IVIG. We observed a 417% increase in IVIG administration (g) over time, attributed mainly to autoimmune diseases. Many indications are still off-label according to FDA recommendations.

Animal models are a key element in disease research and treatment. In the field of neuropsychiatric lupus research, inbred, transgenic and disease-induced mice provide an opportunity to study the pathogenic routes of this multifactorial illness. In addition to achieving a better understanding of the immune mechanisms underlying the disease onset, supplementary metabolic and endocrine influences have been discovered and investigated. The ever-expanding knowledge about the pathologic events that occur at disease inception enables us to explore new drugs and therapeutic approaches further and to test them using the same animal models. Discovery of the molecular targets that constitute the pathogenic basis of the disease along with scientific advancements allow us to target these molecules with monoclonal antibodies and other specific approaches directly. This novel therapy, termed 'targeted biological medication' is a promising endeavor towards producing drugs that are more effective and less toxic. Further work to discover additional molecular targets in lupus' pathogenic mechanism and to produce drugs that neutralize their activity is needed to provide patients with safe and efficient methods of controlling and treating the disease. © The Author(s), 2016.

Background Data on the functional impact of anemia on cardiorespiratory fitness (CRF) and survival in healthy individuals are limited. Our aim was to evaluate the association between anemia thresholds, low CRF, and survival in otherwise healthy adults. Methods Study population included 16 334 apparently healthy subjects attending annual periodic health screening examinations (71 200 annual visits), including exercise stress testing (EST). Anemia was defined by the World Health Organization (WHO) or Beutler and Waalens’ (BW) criteria. Low CRF was defined as the lowest fitness quintile according to the Bruce protocol. Results The mean age was 46±10 years, and 70% were men. Mean Hb levels were 13±1 and 15±1 among women and men, respectively, with higher proportion of anemia among women. The majority of anemic subjects had mild anemia. When analyzing repeated annual visits, anemia was associated with a significant 39% and 64% increased risk of low CRF according the WHO and BW criteria only in women (n=18 672). Baseline anemia at first visit was associated with 2.6- and 1.9-fold increased risk of all-cause mortality using the WHO and BW criteria, exclusively in men (n=11 511). Conclusions Overall, the functional and prognostic impact of anemia is gender dependent, based on the WHO and BW arbitrary criteria, suggesting differing mechanism and responses.

There is much evidence suggesting that an association exists between various autoimmune phenomena and malignant conditions. These phenomena are often referred to as paraneoplastic syndromes. Paraneoplastic syndromes are rare and are not directly caused by the tumor itself or its metastasis but are mediated by soluble factors, such as hormones and cytokines, or humoral or cellular immune mechanisms against tumor cells. Therefore, the clinical manifestations of paraneoplastic syndromes typically occur distant from the underlying malignancy. In addition, autoantibodies can be detected in patients with cancer. Tumor associated antigens may serve in the future as biomarkers. Other more routinely measured antibodies (e.g., ANA, RF) may also appear warrant for investigation when clinical suspicion is raised. Herein we review the main paraneoplastic syndromes and autoantibodies encountered in clinical practice.

To investigate the association between heart rate recovery (HRR) and new-onset atrial fibrillation (AF) in middle-aged adults.Heart rate recovery was calculated using the exercise stress test in 15,729 apparently healthy self-referred men and women who attended periodic health screening examinations between January 2000, and December 2015. All participants completed the maximal exercise stress test according to the Bruce protocol and were followed clinically on a yearly basis for a median of 6.4±4 years. The primary end point was new-onset AF. Participants were grouped according to HRR at 5 minutes, dichotomized at the median value (73 beats/min).Participants with low HRR were older, were more commonly men, had a higher rate of comorbidities, and were less fit. Kaplan-Meier survival analysis revealed that the cumulative probability of AF at 6 years was higher in participants with low HRR (2.1%) than in those with high HRR (0.6%) (log-rank, P.001). Older age, male sex, obesity resting heart rate, and ischemic heart disease were all associated with increased AF risk in a univariate Cox regression model (P.05 for all). Multivariate Cox regression analysis revealed that low HRR was independently associated with increased AF risk (hazard ratio, 1.92; 95% CI, 1.3-2.8; P.001) after adjustment for multiple confounders.Lower HRR is independently associated with the development of new-onset AF during long-term follow-up in middle-aged adults.

Objective Anti-ribosomal-phosphoprotein antibodies (anti-Ribos.P Abs) are detected in 10–45% of NPSLE patients. Intracerebroventricular administration of anti-ribosomal-P Abs induces depression-like behaviour in mice. We aimed to discern the mechanism by which anti-Ribos.P Abs induce behavioural changes in mice. Methods Anti-Ribos.P Abs were exposed to human and rat neuronal cell cultures, as well as to human umbilical vein endothelial cell cultures for a control. The cellular localization of anti-Ribo.P Abs was found by an immunofluorescent technique using a confocal microscope. Identification of the target molecules was undertaken using a cDNA library. Immunohistochemistry and an inhibition assay were carried out to confirm the identity of the target molecules. Neuronal cell proliferation was measured by bromodeoxyuridine, and Akt and Erk expression by immunoblot. Results Human anti-Ribos.P Abs penetrated into human neuronal cells and rat hippocampal cell cultures in vitro, but not to endothelial cells as examined. Screening a high-content human cDNA-library with anti-Ribos.P Abs identified neuronal growth–associated protein (GAP43) as a target for anti-Ribos.P Abs. Ex vivo anti-Ribos.P Abs bind to mouse brain sections of hippocampus, dentate and amygdala. Anti-Ribos.P Abs brain-binding was prevented by GAP43 protein. Interestingly, GAP43 inhibited in a dose-dependent manner the anti-Ribos.P Abs binding to recombinant-ribosomal-P0, indicating mimicry between the ribosomal-P0 protein and GAP43. Furthermore, anti-Ribos.P Abs reduced neuronal cell proliferation activity in vitro (P < 0.001), whereas GAP43 decreased this inhibitory activity by a factor of 7.6. The last was related to Akt and Erk dephosphorylation. Conclusion Anti-Ribos.P Abs penetrate neuronal cells in vitro by targeting GAP43. Anti -Ribos.P Abs inhibit neuronal-cell proliferation via inhibition of Akt and Erk. Our data contribute to deciphering the mechanism for anti-Ribos.P Abs’ pathogenic activity in NPSLE.

Aims The SCORE risk estimation system is used for cardiovascular risk stratification in apparently healthy adults and is based on known cardiovascular risk factors. The purpose of the current study was to evaluate whether exercise capacity can improve the accuracy of the SCORE overall survival risk estimation. Methods and results We investigated 22 878 asymptomatic men and women who were annually screened in a tertiary medical centre. All subjects were free of known ischaemic heart disease, and had completed maximal exercise stress test according to the Bruce protocol. The SCORE risk estimation system was used to evaluate individual cardiovascular risk for all subjects. The primary endpoint was mortality, after exclusion of patients with metastatic cancer during follow-up. The incremental contribution of exercise capacity in predicting the risk of death was evaluated by net reclassification improvement (NRI) and area under the receiver operating curve (AUROC). Mean age of the study population was 47.4 ± 10.3, and 71.6% were men. There were 505 (2.21%) deaths during a mean follow-up of 9.2 ± 4.1 years. Kaplan–Meier survival analysis showed that both SCORE and low exercise capacity were associated with reduced survival. When added to the SCORE risk prediction, exercise capacity allowed more accurate risk stratification: NRI analysis showed an overall improvement of 56.8% in the accuracy of classification and the AUROC increased (0.782 vs. 0.766). Conclusion Both SCORE and exercise capacity are strong independent predictors of all-cause mortality. The addition of exercise capacity to the SCORE risk model can improve the accuracy of the model.

Guillain-Barré syndrome (GBS) is an autoimmune disease of the peripheral nervous system with a typical presentation of acute paralysis and hyporeflexia. Intravenous immunoglobulin (IVIG) and plasma exchange (PLEX) are treatments that have proven to expedite recuperation and recovery of motor function.To describe our experience at one tertiary medical center treating GBS with IVIG and to compare the efficacy of IVIG as the sole treatment versus combined therapy of IVIG and plasma exchange.We reviewed the records of all patients diagnosed with GBS and treated with IVIG at the Sheba Medical Center from 2007 to 2015 and collected data on patient demographics, disease onset and presentation, and treatments delivered. The motor disability grading scale (MDGS) was used to evaluate the motor function of each patient through the various stages of the disease and following therapy.MDGS improvement from admission until discharge was statistically significant (P0.001), as was the regainment of motor functions at 3 and 12 months follow-up compared to the status during the nadir of the disease. The effectiveness of second-line treatment with IVIG following PLEX failure and vice versa was not statistically significant (P0.15).The majority of patients included in this study experienced a significant and rapid improvement of GBS following treatment with IVIG. Combined therapy of PLEX and IVIG was not proven to be effective in patients who encountered a failure of the first-line treatment.

Studies are emerging alluding to the role of intestinal microbiome in the pathogenesis of diseases. Intestinal microbiome is susceptible to the influence of environmental factors such as smoking, and recent studies have indicated microbiome alterations in smokers. The aim of the study was to review the literature regarding the impact of smoking on the intestinal microbiome. A literature review of publications in PUBMED was performed using combinations of the terms "Intestinal/Gut/Gastrointestinal/Colonic" with "Microbiome/Microbiota/Microbial/Flora" and "Smoking/Smoker/Tobacco". We selected studies that were published between the years 2000 and 2016 as our inclusion criteria. Observational and interventional studies suggest that the composition of intestinal microbiome is altered due to smoking. In these studies, Proteobacteria and Bacteroidetes phyla were increased, as well as the genera of Clostridium, Bacteroides and Prevotella. On the other hand, Actinobacteria and Firmicutes phyla as well as the genera Bifidobacteria and Lactococcus were decreased. Smoking also decreased the diversity of the intestinal microbiome. Mechanisms that have been suggested to explain the effect of smoking on intestinal microbiome include: oxidative stress enhancement, alterations of intestinal tight junctions and intestinal mucin composition, and changes in acid-base balance. Interestingly, some smoking-induced alterations of intestinal microbiome resemble those demonstrated in conditions such as inflammatory bowel disease and obesity. Further studies should be performed to investigate this connection. Smoking has an effect on intestinal microbiome and is suggested to alter its composition. This interaction may contribute to the development of intestinal and systemic diseases, particularly inflammatory bowel diseases.

Our understanding of the mechanisms leading to rheumatic diseases is growing at unprecedented pace thanks to the worldwide network of clinical and translational researchers who gather at major scientific meetings to share their progresses. Further, these meetings allow the contamination of unrelated research areas and thus the spreading of ideas, hypotheses, and research tools. The annual meeting of the American College of Rheumatology (ACR) serves this purpose by allowing thousands of rheumatologists, immunologists, health care professionals, and basic scientists to attend the same sessions and present their work. The 2014 ACR meeting was held in Boston, MA, and was attended by over 16,000 participants who had the opportunity to directly witness the presentation of over 3000 abstracts. As such is the case, a full attendance of all update opportunities was not feasible. To fill this gap we arbitrarily selected the abstracts the appeared most interesting in a few fields of interest and we herein discuss the presented data and their further implications. In particular, we were intrigued by research advances in biomarkers for rheumatic diseases, and by advances on Sjögren syndrome, neuropsychiatric systemic lupus erythematosus, fibromyalgia, and B cell mechanisms. While we are well aware of the numerous blind spots that are expected in this type of article, we submit that this is far from a comprehensive overview and refer to the abstract book for a more complete analysis of the presented abstracts.

Obesity and overweight are strongly associated with cardiovascular morbidity and mortality. However, there are limited data on the association between excess weight and the risk of ectopic ventricular activity.We investigated the association between body mass index (BMI) and the risk for ectopic ventricular activity (defined as multiple ventricular premature beats (≥3), ventricular bigeminy, nonsustained ventricular tachycardia or sustained ventricular tachycardia) during exercise stress testing among 22,516 apparently healthy men and women who attended periodic health screening examinations between the years 2000 and 2014. All subjects had completed maximal exercise stress testing annually according to the Bruce protocol. Subjects were divided at baseline into three groups: normal weight (BMI ≥ 18.5 kg/m(2) and25; N = 9,994), overweight (BMI ≥ 25 and 30; N = 9,613) and obese (BMI ≥ 30; N = 2,906).The mean age of study subjects was 47 ± 10 years and 72% were men. Kaplan-Meier survival analysis showed that the cumulative probability for the development of exercise-induced ectopic ventricular activity arrhythmias was highest among obese subjects, intermediate among overweight subjects and lowest among subjects with normal weight (3.4%, 2.7% and 2.2% respectively; p 0.001). Multivariate binary logistic regression with repeated measures of 92,619 ESTs, showed that obese subjects were 33% more likely to have ectopic ventricular arrhythmias during exercise compared with subjects with normal weight (p = 0.005), and that each 1 kg/m(2) increase in BMI was associated with a significant 4% (p = 0.002) increased adjusted risk for exercise-induced ventricular arrhythmias.Obesity is independently associated with increased likelihood of ectopic ventricular arrhythmia during exercise.

Narcolepsy is a neurological disorder characterized by excessive daytime sleepiness. It is caused by the loss of orexin producing neurons in the lateral hypothalamus. Current evidences suggest an autoimmune mediated process causing the specific loss of orexin neurons. The high association of the disease with the HLA DQB1?06:02, as well as the link with environmental factors and are important clues supporting this theory. Recently, the association between the occurrence of the disease and vaccination campaign after the 2009 H1N1 pandemic highlighted the importance to increase the knowledge in the Pandora box of the vaccines. This review discusses the last finding regarding the pathogenesis of the disease and its relationship with the H1N1 vaccines. © 2014 Elsevier Ltd. All rights reserved.

Background: Several studies in animal models and human with obstructive sleep apnea syndrome (OSAS) demonstrated an increase in cancer aggressiveness and mortality. However, there is a need for further clinical evidence supporting a correlation between OSAS and cancer incidence. Objectives: To reveal whether OSAS presence and severity is correlated with cancer incidence in a large homogenous patients’ cohort. Methods: We analyzed a cohort of over 5,000 concurrently enrolled patients, age > 18, with suspected OSAS, from a tertiary medical academic center. Patients underwent whole night polysomnography, the gold standard diagnostic tool for OSAS, and were classified for severity according to the Apnea Hypopnea Index (AHI). Data on cancer incidence were obtained from the Israel National Cancer Registry. A multivariate Cox proportional-hazards analysis, adjusted for age, gender, and BMI, was performed to estimate the hazard-ratio of new cancer incidence. Results: Among 5,243 subjects with a median follow-up of 5.9 years, 265 were diagnosed with cancer. The most prevalent cancers were prostate (14.7%), hematological (12.8%), urothelial (9.4%), colorectal (9%), and breast (8.3%). In subjects who were diagnosed at age below 45 years (n = 1,533), a high AHI (> 57/h) was significantly associated with cancer (HR 3.7, CI 1.12–12.45, p = 0.008). Conclusions: Patients younger than 45 with severe OSAS have a significantly higher all-type cancer incidence than the general population. These results should encourage clinicians to detect and diagnose young patients with suspected OSAS and to recommend cancer screening methods in this high-risk population.

Intravenous immunoglobulins (IVIG) are a biologic product originally developed to treat immunocompromised patients. In the past decades, there has been increased utilization of IVIG in autoimmune conditions. The objectives were to evaluate the clinical use of IVIG in the largest tertiary medical center in Israel and to determine top uses, estimate off-label usage, and assess consumption of this blood product.We conducted an observational, retrospective study involving all patients who received IVIG from 2007 through 2015. Subjects were classified into five groups according to the indication for treatment.A total of 1117 patients were identified. The mean (±SD) ages of adults and children were 55 ± 17 and 8 ± 7 years, respectively. Most common indication for treatment were immune-mediated conditions (54%), followed by secondary immunodeficiency (28%), primary immunodeficiency (10%), infections (4%), and miscellaneous (4%). The main immune-mediated conditions treated were hematologic disorders (305 patients, 27%), neurologic disorders (219 patients, 20%), and rheumatologic conditions (79 patients, 7%). Overall, a significant change in study period was observed in the number of patients (p 0.001), consumption of IVIG (p 0.01), and amount of IVIG administered per patient (p 0.01). Fifty-six percent of the IVIG infusions were given for off-label Food and Drug Administration (FDA) indications.In this study, we demonstrated that immune-mediated conditions represent the majority of indications for treatment with IVIG. We observed a 417% increase in IVIG administration (g) over time, attributed mainly to autoimmune diseases. Many indications are still off-label according to FDA recommendations.

Anti-BLyS treatment with the human belimumab monoclonal antibody was shown to be a safe and effective therapeutic modality in lupus patients with active disease (i.e., without significant neurological/renal involvement) despite standard treatment.To evaluate the "real-life" safety and efficacy of belimumab added to standard therapy in patents with active lupus in five Israeli medical centers.We conducted a retrospective open-labeled study of 36 lupus patients who received belimumab monthly for at least 1 year in addition to standard treatment. Laboratory tests (C3/C4, anti dsDNA autoantibodies, chemistry, urinalysis and complete blood count) were done every 3-4 months. Adverse events were obtained from patients' medical records. Efficacy assessment by the treating physicians was defined as excellent, good/partial, or no response.The study group comprised 36 lupus patients (8 males, 28 females) with a mean age of 41.6 } 12.2 years. Belimumab was given for a mean period of 2.3 } 1.7 years (range 1-7). None of the patients discontinued belimumab due to adverse events. Four patients (11.1%) had an infection related to belimumab. Only 5 patients (13.9%) stopped taking belimumab due to lack of efficacy. The response was excellent in 25 patients (69.5%) and good/partial in the other 6 (16.6%). Concomitantly, serological response (reduction of C3/C4 and anti-dsDNA autoantibodies) was also observed. Moreover, following belimumab treatment, there was a significant reduction in the usage of corticosteroids (from 100% to 27.7%) and immunosuppressive agents (from 83.3% to 8.3%).Belimumab, in addition to standard therapy, is a safe and effective treatment for active lupus patients.

Autoimmunology is a super-specialty of immunology specifically dealing with autoimmune disorders. To assess the extant literature concerning autoimmune disorders, bibliometric and scientometric analyses (namely, research topics/keywords co-occurrence, journal co-citation, citations, and scientific output trends - both crude and normalized, authors network, leading authors, countries, and organizations analysis) were carried out using open-source software, namely, VOSviewer and SciCurve. A corpus of 169,519 articles containing the keyword "autoimmunity" was utilized, selecting PubMed/MEDLINE as bibliographic thesaurus. Journals specifically devoted to autoimmune disorders were six and covered approximately 4.15% of the entire scientific production. Compared with all the corpus (from 1946 on), these specialized journals have been established relatively few decades ago. Top countries were the United States, Japan, Germany, United Kingdom, Italy, China, France, Canada, Australia, and Israel. Trending topics are represented by the role of microRNAs (miRNAs) in the ethiopathogenesis of autoimmune disorders, contributions of genetics and of epigenetic modifications, role of vitamins, management during pregnancy and the impact of gender. New subsets of immune cells have been extensively investigated, with a focus on interleukin production and release and on Th17 cells. Autoimmunology is emerging as a new discipline within immunology, with its own bibliometric properties, an identified scientific community and specifically devoted journals.

Human papillomavirus vaccine (HPVv) is used worldwide for prevention of infection. However several reports link this vaccine, with immune-mediated reactions, especially with neurological manifestations. Our previous results showed that HPVv-Gardasil and aluminum-immunized mice developed behavioral impairments. Studies have shown a positive effect of phospholipid supplementation on depression and cognitive functions in mice. Therefore, our goal was to evaluate the effect of a dietary supplement on vaccine-induced depression. Sixty C57BL/6 female mice were immunized with HPVv-Gardasil, aluminum or the vehicle (n = 20 each group), and half of each group were fed 5 times per week with 0.2 ml of a dietary supplement enriched with phosphatidylcholine. The mice were evaluated for depression at 3 months of age, by the forced swimming test. Both the Gardasil and the aluminum-treated mice developed depressive-like behavior when compared to the control group. The HPVv-Gardasil-immunized mice supplemented with phosphatidylcholine significantly reduced their depressive symptoms. This study confirms our previous studies demonstrating depressive-like behavior in mice vaccinated with HPVv-Gardasil. In addition, it demonstrates the ability of phosphatidylcholine-enriched diet to attenuate depressive-like behavior in the HPVv-Gardasil-vaccinated mice. We suggest that phosphatidylcholine supplementation may serve as a treatment for patients suffering vaccine-related neurological manifestations. © 2016, Springer Science+Business Media New York.

Data regarding travelers with chronic illnesses (TCI) traveling to developing countries is limited.A retrospective cohort study of travelers. We analyzed demographics, travel destinations, travel dates and duration, as well as the medical history (chronic illnesses, chronic medications, and allergies) of the travelers.Of 16,681 travelers evaluated, 3046 (18%) were TCI, of who, 2221 (13%) were taking chronic medications. The percentage of TCI ranged from 4% in the first decade of life to 65% in the 8th decade. The highest number of TCI (1085) was among the 20–30 years age group. The median age (IQR) of TCI was 39.0 (23.1–58.2), compared to 24.2 (22.0–32.1) years, of healthy travelers (p0.001). The major pre-existing medical conditions among TCI were endocrine/metabolic (38%), cardiovascular (26%) and pulmonary illnesses (16%). Within age groups, no difference was found in itinerary and other travel characteristics. However, 20–30 years old TCI, who were using chronic medications had significantly shorter travel duration (P0.001).TCI form a significant proportion of travelers among all age groups and travel destinations. Chronic illnesses appear to have little impact on travel itinerary and characteristics, but chronic medication use is associated with shorter travel duration to developing countries.

Objective Low dose (10–25 mg/week) methotrexate is widely used for the management of systemic inflammatory diseases, and is considered to be relatively safe. Toxicity due to low dose MTX has been reported but is poorly characterized. We describe the clinical features, risk factors, and outcomes of low dose MTX toxicity in a large case series at our center. Patients and methods We conducted a retrospective case series of all adult (> 18 years) patients hospitalized at Sheba Medical Center, between 2005 and 2012 for low dose MTX toxicity. Results We identified 28 patients (age: 70.4 ± 13.7 years, range: 33–88; 20 (71%) females) hospitalized for low dose MTX toxicity. Indications for MTX therapy included: rheumatoid arthritis (39.2%), psoriasis ± arthritis (21.5%), polymyalgia rheumatica (10.8%) and other inflammatory conditions (28.5%). Pancytopenia was the most common manifestation of low dose MTX toxicity detected in 78.5% of the patients. Potential risk factors included acute renal failure, hypoalbuminemia, concurrent use of drugs known to interact with MTX, and dose errors. Serum MTX concentrations (n = 20, mean 0.04 ± 0.07 μg/mL range: 0–0.3) did not correlate with the degree of either neutropenia (r = − 0.36; p = 0.18) or thrombocytopenia (r = 0.44; p = 0.10). Seven (25%) patients died, all from pancytopenia followed by sepsis. Serum MTX concentrations did not differ between the patients who died from MTX toxicity (n = 6; mean: 0.05 ± 0.04 μg/mL) and those who survived the toxicity (n = 14 mean 0.04 ± 0.08; p = 0.45). Conclusions Low-dose MTX toxicity can be life threatening, mainly due to myelosuppression. There is no rationale for MTX therapeutic drug monitoring in the setting of low-dose toxicity.

Cardiac sympathetic denervation is an early nonmotor feature of Parkinson's disease (PD). The aim of the current study was to trace evidence for cardiac dysfunction abnormalities in the premotor phase of PD. We retrospectively reviewed treadmill ergometric tests of a large cohort (n 5 16,841) between 2000 and 2012, that attended the Executive Screening Survey (ESS) at Sheba Medical Center. Heart rate and blood pressure profiles as well as exercise capacity were compared between subjects who later developed PD and age- and sex-matched subjects (ratio 1:2) who did not. We identi- fied 28 subjects (24 males) who developed PD at follow- up. The PD group was older than the group of subjects who did not develop PD on first ergometric test (64.82 6 8.82 vs. 48.91 6 10.60 years, P < 0.001). The time between the first ergometri ct est and motor symptoms onset was 4.64 6 2.86 years. Patients who later devel- oped PD had lower maximal heart rate (P < 0.001) and lower heart rate reserve than healthy controls (P < 0.001); however, compared with age- and sex-matched subjects, subjects who developed PD had similar exercise capacity and heart rate profile during rest, exercise, and recovery, even 1 year before diagnosis. In this study, we did not detect significant signs of sympathetic dysfunction during the premotor phase of PD. V C 2014 International Parkinson and Movement Disorder Society

Smoking is an independent cardiovascular risk factor and correlates with reduced exercise tolerance. However, data on the time dependent effect of smoking cessation on exercise tolerance are limited.We investigated 17,115 men and women who were annually screened at the Institute for Medical Screening of the Chaim Sheba Medical Centre. All subjects had their smoking status documented and performed an exercise stress testing (EST) according to Bruce protocol at each visit. Subjects were divided at baseline into four groups: active smokers (N = 2858), recent quitters (smoking cessation ≤2 years before baseline EST; N = 861), remote quitters (smoking cessation2 years before the baseline EST; N = 3856) and never smokers (N = 9810). Baseline and follow up EST duration were compared among the four groups.Recent quitters demonstrated a 2.4-fold improvement in their EST duration compared with active smokers (improvement of 24 ± 157 vs. 10 ± 157 s, respectively, p = 0.02). Multivariate logistic regression showed that recent quitters were 26% more likely to improve their exercise tolerance compared with active smokers (95% confidence interval (CI) 1.08-1.47, p = 0.003). Assessing smoking status as a time-dependent covariate during four consecutive visits demonstrated that recent quitters were 17% more likely to improve their exercise tolerance compared with active smokers (95% CI 1.02-1.34, p = 0.02), with a less pronounced benefit among remote quitters (hazard ratio = 1.11, 95% CI 1.02-1.21; p = 0.01).Smoking cessation is independently associated with improved exercise tolerance. The benefits of smoking cessation are evident within the first two years of abstinence.

High-density lipoprotein cholesterol (HDL-C) is a strong inverse predictor of cardiovascular events. The aim of the current study was to evaluate the correlation between changes in HDL-C and subsequent cardiovascular events.Study population comprised 13,037 subjects free of cardiovascular disease with a mean follow up of 6 ± 3 years. Low HDL-C was defined as40 mg/dl for men and50mg/dl for women. Participants were divided into three groups based on HDL-C levels at the first and second baseline visits: persistently-low HDL-C (LL); persistently-high HDL-C (HH); and those with high HDL-C in a one visit only: intermittently high HDL-C (LH/HL). The primary endpoint was the first occurrence of a cardiovascular event.A total of 529 (4.1%) incident events occurred during follow-up. HDL-C levels increased significantly between the two landmark visits (47.5 ± 12.6 vs. 48.1 ± 12.2, p0.001). Kaplan-Meier survival analysis showed that the cumulative probability of cardiovascular events at 6 years was highest among subjects in the LL group (7.6%), and similar among LH/HL and HH groups (3.3% and 4%, respectively; log-rank p=0.001). Multivariate Cox regression analysis, with HDL-C as time-dependent covariate, showed that subjects with persistently low HDL-C during follow up experienced a 51% increased cardiovascular risk compared with subjects with persistently high HDL-C (p=0.026). Subjects with intermittently high HDL-C during follow up experienced similar risk to those with persistently high HDL-C (HR=1.02; p=0.89).Variations in HDL-C levels during follow-up are associated with subsequent cardiovascular risk. Patients who retain low HDL-C levels are at the cardiovascular highest risk.