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A large variety of positive outcomes including social adjustment, psychological well-being and health, have been recently closely associated with positivity (POS). On the assumption that differences in the POS degree might be associated with different individual neuroendocrine assets that enables people to cope effectively with stress, the present study examined the association between POS, salivary cortisol and α-Amylase (α-Amy) production in a group of healthy male volunteers university students, respectively scoring high (POS-H, N = 10) and low (POS-L, N = 10) in POS. Participants were selected from a larger sample of 300 students of the Medical School at Sapienza University of Rome on the basis of their positivity level: POS was analysed and the upper and lower 25% were invited to participate in this new study. The findings report a distinct salivary cortisol and α-Amy production in the study population: in comparison to the POS-H group, the POS-L subjects presented a lower salivary cortisol awake response (CAR) and a flattened α-Amy production at 30 and 60 min after awakening. In addition, salivary cortisol and α-Amy areas under the curve (AUCs), which were calculated as indicators of the two subclinical biomarkers production during the first hour after awakening, resulted significantly lower in the POS-L group in comparison to the POS-H group. Further studies on larger and different populations are needed to definitively confirm that the different cortisol and α-Amy secretion patterns between POS-H and POS-L individuals is associated with a potentially better capacity to preserving an adequate quality of life in individuals being equipped with a system apparently able to better respond to external and/or internal stimuli. Lastly, a better understanding of the biological correlates of POS is crucial to design psychological interventions able to take advantage of individuals’ assets and thus to integrate and strengthen the efficacy of traditional medications.

To update the European League Against Rheumatism (EULAR) recommendations for vaccination in adult patients with autoimmune inflammatory rheumatic diseases (AIIRD) published in 2011. Four systematic literature reviews were performed regarding the incidence/prevalence of vaccine-preventable infections among patients with AIIRD; efficacy, immunogenicity and safety of vaccines; effect of anti-rheumatic drugs on the response to vaccines; effect of vaccination of household of AIIRDs patients. Subsequently, recommendations were formulated based on the evidence and expert opinion. The updated recommendations comprise six overarching principles and nine recommendations. The former address the need for an annual vaccination status assessment, shared decision-making and timing of vaccination, favouring vaccination during quiescent disease, preferably prior to the initiation of immunosuppression. Non-live vaccines can be safely provided to AIIRD patients regardless of underlying therapy, whereas live-attenuated vaccines may be considered with caution. Influenza and pneumococcal vaccination should be strongly considered for the majority of patients with AIIRD. Tetanus toxoid and human papilloma virus vaccination should be provided to AIIRD patients as recommended for the general population. Hepatitis A, hepatitis B and herpes zoster vaccination should be administered to AIIRD patients at risk. Immunocompetent household members of patients with AIIRD should receive vaccines according to national guidelines, except for the oral poliomyelitis vaccine. Live-attenuated vaccines should be avoided during the first 6 months of life in newborns of mothers treated with biologics during the second half of pregnancy. These 2019 EULAR recommendations provide an up-to-date guidance on the management of vaccinations in patients with AIIRD.

Background In early childhood, the allergen-specific IgG repertoire is mainly directed to animal and vegetable food molecules and infrequently to airborne molecules. It is unknown whether this early pattern is maintained throughout childhood. Objective To investigate the evolution of IgG and IgE responses to a broad panel of allergenic molecules from birth to age 10yrs. Methods We examined the sera collected between birth and age 10yrs from participants in the German Multicentre Allergy Study, a birth cohort born in 1990. The IgE (cut-off ≥0.30 ISU) and IgG (cut-off ≥0.10 ISU) responses to 35 genuine allergenic molecules were measured with a multiplex microarray approach (ImmunoCAP ISAC™). Results IgE responses were mostly directed against a restricted group of airborne molecules, with a sequence and prevalence hierarchy (Phl p 1 > Bet v 1 > Fel d 1 > Phl p 5 > Der p 2 > Der p 1) largely maintained over time. Conversely, the IgG repertoire was much broader, starting with animal foodborne, then spreading to vegetable foodborne and finally to airborne molecules. A strong and persistent IgG response to a given airborne molecule almost invariably preceded or accompanied an IgE response to that molecule. Conclusions The evolution of IgG and IgE responses throughout childhood differs widely at population level. IgG responses are mostly directed to animal food allergens while IgE responses are dominated by airborne allergens. However, a strong IgG response almost invariably precedes or accompanies the appearance of IgE to the same molecule in specifically sensitized subjects. This article is protected by copyright. All rights reserved.

In the current study, the possible association of positivity (POS), recently defined as general disposition to view life under positive outlook, with immune markers and post-stress modifications, was analyzed. Circulating lymphocyte subsets and serum cytokine levels were evaluated before and after a standard mild acute stress test, in 41 healthy students, previously selected by a questionnaire for their level of POS (high [POS-H] and low [POS-L]). The CD3+ and CD4+ cell frequency was higher in the POS-H students before and after acute stress. CD4+ subpopulation analysis revealed baseline higher terminally differentiated frequency in the POS-H, whereas higher effector memory frequency was present in the POS-L students. Moreover, the frequency of post-stress B cells was higher in the POS-H students. The mild-stress test was associated to an increase of the IL-10 mean values, while mean values of the other cytokines tested did not change significantly. It is tempting to speculate that IL-10 may work as biomarker of response to acute mild stress and that POS-H may be associated to a better capacity of the immune system to contrast the disturbing effects of mild acute stress. Yet further studies on lymphocyte subset absolute number and function of larger and different populations are needed to definitively prove these preliminary observations.

AimTo present a systematic literature review (SLR) on efficacy, immunogenicity and safety of vaccination in adult patients with autoimmune inflammatory rheumatic diseases (AIIRD), aiming to provide a basis for updating the EULAR evidence-based recommendations.MethodsAn SLR was performed according to the standard operating procedures for EULAR-endorsed recommendations. Outcome was determined by efficacy, immunogenicity and safety of vaccination in adult patients with AIIRD, including those receiving immunomodulating therapy. Furthermore, a search was performed on the effect of vaccinating household members of patients with AIIRD on the occurrence of vaccine-preventable infections in patients and their household members (including newborns). The literature search was performed using Medline, Embase and the Cochrane Library (October 2009 to August 2018).ResultsWhile most investigated vaccines were efficacious and/or immunogenic in patients with AIIRD, some were less efficacious than in healthy control subjects, and/or in patients receiving immunosuppressive agents. Adverse events of vaccination were generally mild and the rates were comparable to those in healthy persons. Vaccination did not seem to lead to an increase in activity of the underlying AIIRD, but insufficient power of most studies precluded arriving at definite conclusions. The number of studies investigating clinical efficacy of vaccination is still limited. No studies on the effect of vaccinating household members of patients with AIIRD were retrieved.ConclusionEvidence on efficacy, immunogenicity and safety of vaccination in patients with AIIRD was systematically reviewed to provide a basis for updated recommendations.

Rheumatoid arthritis (RA) is an inflammatory autoimmune disease that can present different extrarticular manifestations involving heart, lungs and kidneys. In recent years there has been a growing awareness of the central role played by the lungs in the onset and progression of RA. In particular interstitial lung disease (ILD) is a common pulmonary manifestation that may be related to the inflammatory process itself, infectious complications and to the treatments used. Management of patients with ILD/RA is still a challenge for clinicians, both synthetic [mainly methotrexate (MTX), leflunomide] and biologic immunosuppressors [mainly anti-tumor necrosis factor (TNF)α] have in fact been related to the onset or worsening of lung diseases with conflicting data. Here we report the case of a 61-year-old male patient with severely active early RA, previously treated with MTX, who developed subacute ILD, along with a review of ILD/RA topic. Tocilizumab (humanized monoclonal antibody against the interleukin-6 receptor) was introduced on the basis of its effectiveness in RA without concomitant MTX and the ability to overcome the profibrotic effects of interleukin (IL)-6. After 3 months of treatment the clinical condition of the patient strongly improved until it reached low disease activity. He no longer complained of cough and dyspnea and bilateral basal crackles were no more present. Considering its distinctive features, tocilizumab, in such a challenging clinical condition, appears to be a safe and effective therapy, thus it enables RA remission without deteriorating ILD, at 1-year follow up, as confirmed by ultrasonography of the affected joints and chest high-resolution computed tomography (HRCT).

A certain number of studies were carried out to address the question of how dysbiosis could affect the onset and development of rheumatoid arthritis (RA), but little is known about the reciprocal influence between microbiota composition and immunosuppressive drugs, and how this interaction may have an impact on the clinical outcome. The aim of this study was to characterize the intestinal microbiota in a groups of RA patients treatment-na&iuml, ve, under methotrexate, and/or etanercept (ETN). Correlations between the gut microbiota composition and validated immunological and clinical parameters of disease activity were also evaluated. In the current study, a 16S analysis was employed to explore the gut microbiota of 42 patients affected by RA and 10 healthy controls. Disease activity score on 28 joints (DAS-28), erythrocyte sedimentation rate, C-reactive protein, rheumatoid factor, anti-cyclic citrullinated peptides, and dietary and smoking habits were assessed. The composition of the gut microbiota in RA patients free of therapy is characterized by several abnormalities compared to healthy controls. Gut dysbiosis in RA patients is associated with different serological and clinical parameters, in particular, the phylum of Euryarchaeota was directly correlated to DAS and emerged as an independent risk factor. Patients under treatment with ETN present a partial restoration of a beneficial microbiota. The results of our study confirm that gut dysbiosis is a hallmark of the disease, and shows, for the first time, that the anti-tumor necrosis factor alpha (TNF-&alpha, ) ETN is able to modify microbial communities, at least partially restoring a beneficial microbiota.

Background: A timely diagnosis and a suitable therapy allow a better control of disease activity and limit joint damage in autoimmune arthritis. Biological therapies played a key role, modifying disease natural history. However, the use of these drugs implies several risks and increases health-care costs [1]. This has raised a question: could be possible, in patients in a state of sustained remission or low disease activity (LDA), choose an optimized regimen of treatment? Recommendations provided by EULAR in 2013 includes this possibility, especially if biologic therapy is in association with DMARDs [2]. While optimized regimen has been attempted in different clinical trials with good results, strong evidences are currently lacking [3]. Objectives: The aim of our study was to analyse the effectiveness of optimization of biologic therapies in a cohort of patients with Rheumatoid and Psoriasic Arthritis (RA and PA). Methods: We retrospectively included patients undergoing optimized therapy in a cohort of 328 outpatients (190 RA, 128 PA) treated with first-line biologic therapy from 2006 to 2017. Optimization was considered as predefined dose downtitration and/or expansion of dose interval in patients with a sustained remission or LDA (DAS 28 -ESR 20% over baseline or by the onset of at least one tender and swollen joint. Our principal end-points were: (I) estimate the proportion of subjects able to optimize therapy (II) define the rate of relapse at 6–12 and 24 months follow-up (FU) in patients undergoing optimization (III) compare the effectiveness of optimized therapy in RA and PA patients and value the rate of optimization in relation to different biologic drugs. Survival analysis (Kaplan-Meier Curves) and Chi Square test were used and a p value Results: During FU, 15/190 (8%) RA patients and 16/138 (12%) PA patients reached a persistent LDA or remission and started the optimized biologic therapy. In survival analysis, rates of relapse at 6 months were 10 % and 0% in RA ad PA respectively, increasing to 21% and 8% at 12 months and finally to 48 % and 34% at 24 months. No significant differences emerged between the two groups. The use of Etanercept was associated with higher possibility to optimize biologic treatment (p=0.007). Conclusions: Biologic therapy optimization is a workable option in RA ad PA patients who reached persistent remission or LDA. In our cohort Etanercept seems to be the most promising drug. Further studies are needed to better define the predictive factors of response in order to identify eligible patients. References [1] Keystone EC. Safety of biologic Therapies – an update. J. of Rheumatol2005;32(Supplement 74):8–12. [2] Smolen JS, Landewe R, Breedveld FC, et al. EULAR recommendations for the management of rheumatoidarthritis with synthetic and biological disease-modifying antirheumatic drugs: 2013 update. Ann Rheum Dis2014;73:492–509. [3] Maneiro JR, Perez-Pampin E, Salgado E, et al. Observational study of optimization of biologic therapies in rheumatoid arthritis: a single-centre experience. Rheumatol Int2014;34(8):1059–63. Disclosure of Interest: None declared

Background: Primary immunodeficiencies (PIDs) are generally characterized by recurrent infections; however they may be complicated by other clinical disorders such as allergy, autoimmunity, and lymphoproliferation. In particular, autoimmunity may be the first manifestation of the disease in patients with low serum immunoglobulins (Ig) levels. Here we describe a group of patients that share features of immunodeficiency and autoimmunity. Materials and Methods: All patients went through a complete T and B cell subset characterization and a B cell function analysis in the peripheral blood by flow-cytometry. B cell proliferation and plasma cell differentiation was measured, in vitro, after CpG stimulation for 7 days as previously described. Semi-quantitative PCR analysis for AID and UNG expression as well as serum levels of BAFF were carried out in order to better define the diagnosis. Results: Immunological and molecular analysis did not lead to the identification of known molecular defect typical of Hyper IgM syndrome. A comparative study of the peripheral blood B cell subsets between patients and healthy donors showed that in patients with autoimmune manifestations all circulating B cells expressed high amounts of surface IgM. Conclusions: These results suggest that the increased IgM expression on circulating B cells, reflecting B cell activation, might identify a clinical condition characterized by hyper IgM serum levels of unknown molecular defects, associated with susceptibility to infections and autoimmunity.

Cellular and humoral immune responses to tetanus-diphtheria vaccine (Td) were assessed in human leukocyte antigen (HLA)-typed Italian military personnel who received multiple concomitant vaccines. Td-specific antibodies and T-lymphocytes were measured in individuals with one (group-1) and more than one (group-2) Td boosters. A third group (group-3), who received several vaccines, but not Td, was studied to verify the hypothesis of the polyclonal B-cell activation as mechanism for antibody persistence. The antibody response to Td toxoids was higher in group-1, who showed lower baseline antibody levels, than in group-2 subjects. The antibody response to tetanus was higher than to diphtheria toxoid in both groups. No correlation between antibody and cellular response, and no interference in the response to Td by co-administration of different vaccines were observed. HLA-DRB1∗01 allele was detected at significant higher frequency in subjects unable to double the baseline anti-diphtheria antibody levels after the vaccination. Anti-tetanus and diphtheria antibodies half-lives were assessed and the long-lasting persistence above the threshold for protection (0.1 IU/ml) was estimated in over 65 and 20 years, respectively. No significant increase of anti-diphtheria antibodies was observed in consequence of polyclonal B-cell activation. This study emphasizes the duration of Td vaccination-induced seroprotection, suggesting that re-vaccination should probably be performed at intervals longer than 10 years. No reciprocal interference by concomitantly administered vaccines has been observed. HLA-DRB1∗01 allele was significantly associated with anti-diphtheria defective response. Finally, this study does not confirm that anti-diphtheria antibody levels are maintained by polyclonal B-cell activation. Clinical trial registry: The study was registered with NCT01807780.

Summary Meningococcal polysaccharide (Men-Ps) vaccine immunogenicity following either primary immunization or revaccination in adults was evaluated. The study population consisted of subjects who have received tetravalent Men-Ps vaccine once (group 1) or at least twice, with a 2–6 dose range (group 2). Human leucocyte antigen (HLA)-typing was performed by polymerase chain reaction and specific immunoglobulin (Ig)G was measured by enzyme-linked immunosorbent assay. Nine months post-immunization, the percentages of individuals with levels of anti-Men-Ps IgG ≥ 2 µg/ml were comparable in both groups, with the exception of anti-Men-PsW135 IgG, which were significantly higher in group 2. The percentage of subjects doubling IgG levels at 9 months was significantly higher in group 1. The high baseline anti-Men-Ps antibody levels negatively influenced the response to revaccination, suggesting a feedback control of specific IgG. The calculated durability of anti-Men-Ps IgG was 2·5–4·5 years, depending on the Men-Ps, following a single vaccine dose. No interference by other vaccinations nor HLA alleles association with immune response were observed. This study confirms that Men-Ps vaccine in adults is immunogenic, even when administered repeatedly, and underlines the vaccine suitability for large-scale adult immunization programmes that the higher costs of conjugate vaccines may limit in developing countries.

Immunogenicity of 13-valent pneumococcal polysaccharide (PnPS) conjugate vaccine (PCV13) was evaluated in 38 rheumatoid arthritis patients under immunosuppressive treatment and 20 healthy controls (HC). Antibodies to all PnPS and diphtheria-toxin analogue conjugate protein were measured pre- (T0), 1 (T1), 6 (T2), 12 (T3) months post-immunization. Patients and HC had similar response to individual PnPS. Mean antibody levels to all PnPS but one doubled at T1 compared with T0, with T3 persistence for only 8-7/13 PnPS. Baseline antibody levels was inversely associated with the rate of responders at T1 (T1/T0≥2) to 11/13 PnPS. Few subjects reached protective IgG levels against some serotypes frequently isolated in Italian patients with invasive pneumococcal disease. Antibody response was not influenced by therapy, except the one to PS7F, which was reduced by tumor necrosis factor-α-inhibitors. Vaccination increased also anti-diphtheria IgG. Despite this study substantially confirmed the PCV13 immunogenicity in immunocompromised patients, it also revealed some limitations.

In higher vertebrates, mucosal sites at the border between the internal and external environments, directly interact with bacteria, viruses, and fungi. Through co-evolution, hosts developed mechanisms of tolerance or ignorance toward some infectious agents, because hosts established "gain of function" interactions with symbiotic bacteria. Indeed, some bacteria assist hosts in different functions, among which are digestion of complex carbohydrates, and absorption and supply of vitamins. There is no doubt that microbiota modulate innate and acquired immune responses starting at birth. However, variations in quality and quantity of bacterial species interfere with the equilibrium between inflammation and tolerance. In fact, correlations between gut bacteria composition and the severity of inflammation were first described for inflammatory bowel diseases and later extended to other pathologies. The genetic background, environmental factors (e.g., stress or smoking), and diet can induce strong changes in the resident bacteria which can expose the intestinal epithelium to a variety of different metabolites, many of which have unknown functions and consequences. In addition, alterations in gut permeability may allow pathogens entry, thereby triggering infection and/or chronic inflammation. In this context, a local event occurring at a mucosal site may be the triggering cause of an autoimmune reaction that eventually involves distant sites or organs. Recently, several studies attributed a pathogenic role to altered oral microbiota in rheumatoid arthritis (RA) and to gut dysbiosis in spondyloarthritis (SpA). There is also growing evidence that different drugs, such as antibiotics and immunosuppressants, can influence and be influenced by the diversity and composition of microbiota in RA and SpA patients. Hence, in complex disorders such RA and SpA, not only the genetic background, gender, and immunologic context of the individual are relevant, but also the history of infections and the structure of the microbial community at mucosal sites should be considered. Here the role of the microbiota and infections in the initiation and progression of chronic arthritis is discussed, as well as how these factors can influence a patient's response to synthetic and biologic immunosuppressive therapy.

ObjectivesThe aims of this study were to update the evidence on the incidence and prevalence rates of vaccine preventable infections (VPI) in patients with autoimmune inflammatory rheumatic diseases (AIIRD) and compare the data to the general population when available.MethodsA literature search was performed using Medline, Embase and Cochrane library (October 2009 to August 2018). The primary outcome was the incidence or prevalence of VPI in the adult AIIRD population. Meta-analysis was performed when appropriate.ResultsSixty-three publications out of 3876 identified records met the inclusion criteria: influenza (n=4), pneumococcal disease (n=7), hepatitis B (n=10), herpes zoster (HZ) (n=29), human papillomavirus (HPV) infection (n=13). An increased incidence of influenza and pneumococcal disease was reported in patients with AIIRD. HZ infection-pooled incidence rate ratio (IRR) was 2.9 (95% CI 2.4 to 3.3) in patients with AIIRD versus general population. Among AIIRD, inflammatory myositis conferred the highest incidence rate (IR) of HZ (pooled IRR 5.1, 95% CI 4.3 to 5.9), followed by systemic lupus erythematosus (SLE) (pooled IRR 4.0, 95% CI 2.3 to 5.7) and rheumatoid arthritis (pooled IRR 2.3, 95% CI 2.1 to 2.6). HPV infection-pooled prevalence ratio was 1.6, 95% CI 0.7 to 3.4 versus general population, based on studies mainly conducted in the SLE population in Latin America and Asia. Pooled prevalence of hepatitis B surface antigen and hepatitis B core antibody in patients with AIIRD was similar to the general population, 3%, 95% CI 1% to 5% and 15%, 95% CI 7% to 26%, respectively.ConclusionCurrent evidence shows an increased risk of VPI in patients with AIIRD, emphasising that prevention of infections is essential in these patients.

Autoimmune diseases such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA) and psoriatic arthritis (PsA) are chronic inflammatory disorders of unknown etiology characterized by a wide range of abnormalities of the immune system that may compromise the function of several organs, such as kidney, heart, joints, brain and skin. Corticosteroids (CCS), synthetic and biologic immunosuppressive agents have demonstrated the capacity to improve the course of autoimmune diseases. However, a significant number of patients do not respond or develop resistance to these therapies over time. P-glycoprotein (P-gp) is a transmembrane protein that pumps several drugs out of the cell, including CCS and immunosuppressants; thus, its over-expression or hyper-function has been proposed as a possible mechanism of drug resistance in patients with autoimmune disorders. Recently, different authors have demonstrated that P-gp inhibitors, such as cyclosporine A (CsA) and its analogue Tacrolimus, are able to reduce P-gp expression and or function in SLE, RA and PsA patients. These observations suggest that P-gp antagonists could be adopted to revert drug resistance and improve disease outcome. The complex inter-relationship among drug resistance, P-gp expression and autoimmunity still remains elusive.

Therapeutic antibodies have been used since the end of nineteenth century, but their use is progressively increased and recently, with the availability of monoclonal antibodies, they are successfully employed in a large disease spectrum, which transversally covers different fields of medicine. Hyperimmune polyclonal immune globulin has been used against infectious diseases, in a period in which anti-microbial drugs were not yet available, and it still maintains a relevant place in prophylaxis/therapy. Although immune globulin should be considered life-saving as replacement therapy in humoral immunodeficiencies, its place in the immune-modulating treatment is not usually first-choice, but it should be considered as support to standard approved treatments. Despite therapeutic monoclonal antibodies have been lastly introduced in therapy, their extreme potentiality is reflected by the large number of approved molecules, addressed toward different immunological targets and able to heavily influence the prognosis and quality of life of a wide range of different diseases.

Biologic drugs for the management of rheumatoid arthritis (RA) have revolutionized the therapeutic armamentarium with the development of several novel monoclonal antibodies, which include murine, chimeric, humanized, fully human antibodies and fusion proteins. These biologics bind to their targets with high affinity and specificity. Since 1998, nine different biologics have been approved by the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) for the treatment of RA, and several others are in different stages of clinical trials. This field is in continuous evolution and new biologics are tested every year. Therefore a precise analysis is required in order to have a detailed and updated state of the art of this field. In this review, our main aim is to analyse all available biological therapies that are FDA and EMA approved for the treatment of RA and also those that are in clinical trials for the management of RA patients.

Background Lymphocyte expansion and true lymphocytosis are commonly observed in the everyday clinical practice. The meaning of such phenomenon is often poorly understood so that discrimination between benign and malignant lymphocytosis remains difficult to establish. This is mainly true when lymphocytosis rises in patients affected by immune-mediated chronic inflammatory diseases under immunosuppressive treatment, conditions potentially associated with lymphomagenesis. In this brief report the development of mild T CD4pos lymphocytosis in a group of patients with chronic arthritis under anti-TNF-α treatment is described. Methods Two hundred eight rheumatoid arthritis (RA) and psoriatic arthritis (PsA) patients have been evaluated longitudinally for at least 1-year before and 2-years after anti-TNF-α therapy introduction for the possible appearance of a lymphocyte expansion. In patients who developed lymphocyte expansion, T, B and NK cells were analysed. Results Twenty-five out of 208 (12%) subjects developed a mild T CD4pos lymphocytosis, during anti-TNF-α therapy, which reverted after its interruption. Higher lymphocyte count, more frequent use of steroids and shorter disease duration, before biological therapy start, have emerged as risk factors for lymphocytosis development. Conclusions This is the first longitudinal cohort study evaluating the onset of lymphocytosis in RA and PsA patients under anti-TNF-α treatment and its possible clinical relevance. A mild T CD4pos lymphocytosis has been observed in 12% of RA and PsA patients probably related to anti-TNF-α treatment as previously reported by anecdotal cases. Patients with higher baseline lymphocyte count, use of steroids and shorter disease duration before the introduction of biologic therapy, seem to be prone to develop this laboratory reversible abnormality.

Anecdotal case reports, amplified by mass media and internet-based opinion groups, have recently indicated vaccinations as possibly responsible for autoimmunity/lymphoproliferation development. Multiply vaccinated Italian military personnel (group 1, operating in Italy, group 2, operating in Lebanon) were followed-up for nine months to monitor possible post-vaccine autoimmunity/lymphoproliferation onset. No serious adverse event was noticed in both groups. Multivariate analysis of intergroup differences only showed a significant association between lymphocyte increase and tetanus/diphtheria vaccine administration. A significant post-vaccine decrease in autoantibody positivity was observed. Autoantibodies were also studied by microarray analysis of self-proteins in subjects exposed to ≥4 concurrent vaccinations, without observing significant difference among baseline and one and nine months post-vaccine. Moreover, HLA-A2 subjects have been analyzed for the possible CD8T-cell response to apoptotic self-epitopes, without observing significant difference between baseline and one month post-vaccine. Multiple vaccinations in young adults are safe and not associated to autoimmunity/lymphoproliferation onset during a nine-month-long follow-up.

Light beams carrying orbital angular momentum are key resources in modern photonics. In many applications, the ability of measuring the complex spectrum of structured light beams in terms of these fundamental modes is crucial. Here we propose and experimentally validate a simple method that achieves this goal by digital analysis of the interference pattern formed by the light beam and a reference field. Our approach allows one to characterize the beam radial distribution also, hence retrieving the entire information contained in the optical field. Setup simplicity and reduced number of measurements could make this approach practical and convenient for the characterization of structured light fields., 8 pages (including Methods and References), 6 figures

A 30-year-old woman affected by Mixed Connective Tissue Disease with scleroderma spectrum developed a facial eruption, a clinical and histological characteristic of subacute cutaneous lupus erythematosus (SCLE). Speckled anti-nuclear antibodies, high-titer anti-ribonucleoprotein1, anti-Sm, anti-Cardiolipin (aCL) IgG/IgM, and anti-Ro/SSA antibodies were positive. SCLE was resistant to Azathioprine, Hydroxychloroquine, and Methotrexate while Mycophenolate Mofetil was suspended due to side effects. Subsequently, the patient was treated with three cycles of therapeutic plasma exchange (TPE) followed, one month after the last TPE, by the anti-CD20 antibody Rituximab (RTX) (375 mg/m2weekly for 4 weeks). Eight and 16 months later the patient received other two TPE and RTX cycles, respectively. This therapeutic approach has allowed to obtain a complete skin healing persistent even after 8-month follow-up. Moreover, mitigation of Raynaud's phenomenon, resolution of alopecia, and a decline of aCL IgG/IgM and anti-Ro/SSA antibodies were observed.

In the case of a large-scale nuclear or radiological incidents a reliable estimate of dose is an essential tool for providing timely assessment of radiation exposure and for making life-saving medical decisions. Cytogenetics is considered as the “gold standard” for biodosimetry. The dicentric analysis (DA) represents the most specific cytogenetic bioassay. The micronucleus test (MN) applied in interphase in peripheral lymphocytes is an alternative and simpler approach. A dose-effect calibration curve for the MN frequency in peripheral lymphocytes from 27 adult donors was established after in vitro irradiation at a dose range 0.15–8 Gy of 137 Cs gamma rays (dose rate 6 Gy min −1 ). Dose prediction by visual scoring in a dose-blinded study (0.15–4.0 Gy) revealed a high level of accuracy ( R = 0.89). The scoring of MN is time consuming and requires adequate skills and expertise. Automated image analysis is a feasible approach allowing to reduce the time and to increase the accuracy of the dose estimation decreasing the variability due to subjective evaluation. A good correlation ( R = 0.705) between visual and automated scoring with visual correction was observed over the dose range 0–2 Gy. Almost perfect discrimination power for exposure to 1–2 Gy, and a satisfactory power for 0.6 Gy were detected. This threshold level can be considered sufficient for identification of sub lethally exposed individuals by automated CBMN assay.

Background Hepatitis B virus (HBV) reactivation in patients positive for antibody to HB core antigen (anti-HBc), negative for HB surface antigen (HBsAg) and HBV-DNA (potential occult HBV carriers), treated with anti-tumor necrosis factor (TNF)α, is a debated question. The aim of the study was to evaluate the safety of anti-TNFα therapy in anti-HBc positive/HBsAg negative subjects with rheumatoid arthritis (RA) and spondyloarthropathy (SpA). Methods All consecutive HBsAg negative RA and SpA outpatients referring to the Immuno-Rheumatology Institute at the S. Andrea hospital, Sapienza, University of Rome who had to undergo anti-TNFα therapy. Results Among the 169 enrolled subjects, 20 (12%) were potential occult HBV carriers (anti-HBc positive, HBsAg and HBV-DNA negative patients with or without anti-HBs). During the follow-up (mean ± SD 45 ± 22 months), aminotransferases and HBV-DNA, tested every two and six months respectively, did not change. Conclusion This study confirms the substantial safety of anti-TNFα therapy in potential occult HBV carriers RA and SpA patients.

Vaccinations have been traditionally considered a risk factor for the induction/reactivation of autoimmune diseases. A Medline search through key words "vaccinations and autoimmune diseases" from 1947 through December 2009 was conducted. Until now, vaccination effects in autoimmune diseases have only been studied in over 5000 patients. Vaccinations generally did not induce worsening of disease activity in patients with multiple sclerosis, systemic lupus erythematosus, rheumatoid arthritis, insulin-dependent-diabetes-mellitus, chronic arthritis in children, vasculitides, and myasthenia gravis, whereas immunogenicity, although protective, was generally lower than in normal controls, depending on disease severity and immunosuppressive therapy. Data are very poor on the efficacy.

Background Studies of a limited number of allergens suggested that nonsensitized children produce IgG responses mainly to foodborne allergens, whereas IgE-sensitized children also produce strong IgG responses to the respective airborne molecules. Objective We sought to systematically test the hypothesis that both the route of exposure and IgE sensitization affect IgG responses to a broad array of allergenic molecules in early childhood. Methods We examined sera of 148 children participating in the Multicentre Allergy Study, a birth cohort born in 1990. IgG to 91 molecules of 42 sources were tested with the ImmunoCAP Solid-Phase Allergen Chip (ISAC; TFS, Uppsala, Sweden). IgE sensitization at age 2 and 7 years was defined by IgE levels of 0.35 kU A /L or greater to 1 or more of 8 or 9 extracts from common allergenic sources, respectively. Results The prevalence and geometric mean levels of IgG to allergenic molecules in nonsensitized children were lower at age 2 years than in IgE-sensitized children, and they were extremely heterogeneous: highest for animal food (87% ± 13%; 61 ISAC Standardized Units [ISU], [95% CI, 52.5-71.5 ISU]), intermediate for vegetable food (48% ± 27%; 13 ISU [95% CI, 11.2-16.1 ISU]), and lowest for airborne allergens (24% ± 20%; 3 ISU [95% CI, 2.4-3.4 ISU]; P for trend P for trend 4 antibodies were infrequent ( Conclusion The children's repertoire of IgG antibodies at 2 years of age to a broad array of animal foodborne, vegetable foodborne, and airborne allergenic molecules is profoundly dependent on the route of allergen exposure and the child's IgE sensitization status and only marginally involves the IgG 4 isotype.

INTRODUCTION Aeromedical evacuation of patients affected by severe infectious diseases inside an aircraft transit isolator (ATI) system is at potential risk of motion sickness (MS). A test flight was then conducted to quantify this risk during the transfer of an Ebola patient from West Africa to Italy. CASE REPORT A mannequin was inserted inside an ATI and instrumented to provide acceleration parameters throughout the test flight. The analysis of the data predicted a MS incidence of about 2% for a 6-h flight, so the decision to use anti-MS drugs only in selected cases was taken (i.e., those with positive past history of MS, gastrointestinal disorders, or residual carsickness due to previous ambulance run). On this basis, an actual aeromedical evacuation of an Ebola patient was successfully performed without the use of any anti-MS drugs. DISCUSSION During aeromedical evacuation with ATI systems, the patient's risk of MS should be evaluated on an individual basis and calibrated according to the specific exposure to motion evoked by the flight platform used. Due to the possible onset of untoward effects, prevention with anti-MS drugs in these patients should be limited to selected cases.

The purpose of this study was to examine the longitudinal relationship between Positivity (POS), defined as a stable disposition to view at experience under a positive outlook, and physical and psychological functioning in a sample of cancer patients immediately after diagnosis and one year later.A total of 110 patients (40% males) with pulmonary, colorectal and breast cancer, aged 30-75 (M age = 59.62; SD = 10.33), have been prospectively enrolled between 2012 and 2013, at the S. Andrea Hospital in Rome. All patients were previously aware of their diagnosis. A follow-up one year after diagnosis was conducted. We used structural equation modeling in order to analyse the specific effects of POS on functioning impairment from diagnosis to follow up.POS was associated with less functioning impairment both at diagnosis and follow-up assessments. Furthermore, POS level at diagnosis continued to be associated with less functioning impairment one year later, after controlling for its stability.Patients with higher level of POS tended to report less symptoms associated with negative affect such as anxiety and despondency and to preserve their habitual relationships and social roles. POS may act as a basic disposition that sustains patients' efforts to deal efficaciously with severe illness, by complying with medical treatment and using cognitive strategies that enable individuals to cope with concurrent and prospective challenges of illness.

Twenty consecutive rheumatoid arthritis (RA) patients (mean age 50.4 +/- 10.5 years; 17 females; mean disease duration 5.78 +/- 3.75 years) enrolled for tumor necrosis factor-alpha (TNF-alpha) blockers therapy (10 infliximab and 10 etanercept) were selected. Before starting therapy, 3 and 6 months thereafter all patients were evaluated for disease activity score (DAS), erythrocyte sedimentation rate (ESR), serum levels of C-reactive protein (CRP), interleukin-6 (IL-6), nerve growth factor (NGF), and brain-derived neurotrophic factor (BDNF). After 3 and 6 months a significant reduction in DAS, ESR, CRP, and IL-6 was observed, whereas no significant differences of NGF and BDNF serum levels were found. These preliminary results confirm that TNF-alpha blockers significantly improve disease activity and inflammation in RA; nevertheless further studies are needed to explain the mechanisms regulating NGF and BDNF release in RA patients treated with TNF-alpha blockers.

Objective To evaluate immunological safety and immunogenicity of influenza vaccine administration in patients with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). Patients and methods Twenty-four patients with low and/or stable disease activity 14 with SLE (mean age 43.42 ± 12.18 years; 13 women) and 10 with RA (mean age 51 ± 14.57 years; 9 women), diagnosed on the basis of the American College of Rheumatology criteria, have been immunized with trivalent split influenza vaccine without adjuvant. Further 24 non-vaccinated patients, 14 with SLE and 10 with RA, and 10 vaccinated healthy subjects, all age- and sex-matched, were used as controls. The patients underwent clinical and laboratory (specific anti-influenzavirus antibodies, auto-antibodies, peripheral blood lymphocyte subpopulations) evaluation before and 30 days after vaccination; auto-antibodies were also assessed at 90 days and disease activity at 90 and 180 days. Results The specific antibody response towards the three used antigens (A/New Caledonia/20/99, A/Moscow/10/99, and B/Shangdong/7/97) significantly increased in both patients and healthy controls, without any significant difference between them. No significant difference could instead be observed on the clinical activity, auto-antibodies, and peripheral blood lymphocyte subpopulations before and after vaccination, and between patients and controls. Conclusions Trivalent split influenza vaccine without adjuvant seems to be safe and immunogenic in patients with SLE and RA, provided that only patients with low and/or stable disease activity are selected.

Systemic-onset JRA is characterized by spiking fevers lasting more than two weeks, typically occurring once, twice each day, with temperature returning to the normal or below normal. There are no specific diagnostic tests for systemic JRA. High level of serum ferritin is the most important, no specific, diagnostic finding associated.

Systemic inflammatory rheumatic diseases are associated with an increased risk of malignancy, in particular of lymphoproliferative disorders. Chronic inflammation, due to the disease itself, generates a microenvironment able to promote cancer development, but it is still controversial whether immunosuppressive therapy may contribute to carcinogenesis. The aim of the study was to evaluate the risk of malignancy in 399 patients affected by rheumatoid arthritis (RA), psoriatic arthritis and ankylosing spondylitis, all treated with either tumor necrosis factor α-inhibitors plus disease-modifying anti-rheumatic drugs (DMARDs) or DMARDs alone. The risk of malignancy in this cohort of patients, observed in the period between 2005 and 2011 at S. Andrea Hospital-Sapienza University of Rome, was compared with that of the general Italian population, matched for age, sex, and area of residence. Fourteen (3.5%) malignancies, five of which were hematologic, have been observed. The overall cancer risk was not significantly increased in comparison to the general population, whereas the risk of hematologic malignancies appeared significantly higher in RA patients (SIR 4.94, 95% CI 1.35-12.64), particularly in female gender (SIR 6.9, 0.95% CI 1.88-17.66). No significant association between therapy and malignancy was demonstrated in RA patients.

Purpose: Anthrax is caused by Bacillus anthracis, which can naturally infect livestock, wildlife and occupationally exposed humans. However, for its resistance due to spore formation, ease of dissemination, persistence in the environment and high virulence, B. anthracis has been considered the most serious bioterrorism agent for a long time. During the last century anthrax evolved from limited natural disease to potentially global threat if used as bioweapon. Several factors may mitigate the consequences of an anthrax attack, including 1. the capability to promptly recognize and manage the illness and its public health consequences; 2. the limitation of secondary contamination risk through an appropriate decontamination; and 3. the evolution of genotyping methods (for microbes characterization at high resolution level) that can influence the course and/or focus of investigations, impacting the response of the government to an attack. Methods: A PubMed search has been done using the key words “bioterrorism anthrax”. Results: Over one thousand papers have been screened and the most significant examined to present a comprehensive literature review in order to discuss the current knowledge and strategies in preparedness for a possible deliberate release of B. anthracis spores and to indicate the most current and complete documents in which to deepen. Conclusions: The comprehensive analysis of the two most relevant unnatural anthrax release events, Sverdlovsk in the former Soviet Union (1979) and the contaminated letters in the USA (2001), shows that inhalational anthrax may easily and cheaply be spread resulting in serious consequences. The damage caused by an anthrax attack can be limited if public health organization, first responders, researchers and investigators will be able to promptly manage anthrax cases and use new technologies for decontamination methods and in forensic microbiology. Keywords: Anthrax history, Bioweapon, Disease, Decontamination, Microbial forensics