Influenza Vaccination in Patients with Rheumatoid Arthritis under treatment with TNFα Blockers or co-stimulus Inhibitor

Influenza vaccination in patients with rheumatoid arthritis under treatment with TNFα blockers or co-stimulus inhibitors Objective To evaluate the safety and the immunogenicity of the trivalent seasonal non-adjuvanted anti-influenza vaccine in rheumatoid arthritis RA patients receiving distinct classes of anti tumor necrosis factor -TNF agents or inhibitors of co-stimulus compared with patients with RA or SLE receiving DMARDs and healthy controls and the effect of a simultaneous 23valent anti-pneumococcal or pandemic monovalent MF59-H1N1adjuvanted vaccine. Methods 85 patients with RA, under treatment with TNFα blockers or inhibitors of co-stimulus, all with stable disease (under the same treatment during the last six months), were immunized at least once with nonadjuvanted trivalent influenza vaccine during three consecutive influenza seasons and compared with 42 HC. In the second season 30 RA patients (13 HC) received simultaneously also adjuvanted pandemic H1N1 vaccination. In the first and third season, instead, respectively 19 and 15 RA (10 and 6 HC) patients received simultaneously also polysaccaride pneumococcal vaccination. In the last season 9 RA and 16 SLE under treatment with DMARDS were also enrolled. Sera were analyzed by hemagglutination-inhibition (HAI) test, according to standard procedures, and vaccine immunogenicity was evaluated according to the Committee for Human Medicinal Products (CHMP) guidelines. Seroprotection, seroconversion (SC), geometric mean titre (GMT), GMT increase, T-reg cells, anti-nuclear antibodies (ANA), adverse events and disease acrivity (according to clinimetric indices) were evaluated at baseline and at 30 and 180 days after vaccination/s. In the second season a study on T cell memory subset modification and aspecific cellular immune response was performed in a patient soubgroup. Moreover the effect of the polisaccaride vaccine on cellular immune response has been analyzed on stimulated PBMC in vitro through cytofluorimetry and ELISA. Results Safety No severe adverse events, ANA appearance/increase or disease reactivation were observed during the 3 influenza seasons. Antibodies 2008/2009: RA patients did not fulfill any immunogenity criteria for A/Brisbane/59/07 (H1), 1 for B/Florida/4/06 , and 3 for A/Brisbane/10/07 (H3). HC, instead, met all the 3 criteria for A/Brisbane/59/07 (H1) and A/Brisbane/10/07 (H3) and only one for B/Florida/4/06. However, the mean increase in geometric mean titer was not statistically different between RA and HC for any antigen. 2009/2010: Both HC and RA patients fulfilled all the 3 immunogenity criteria for the seasonal (A/Brisbane/59/07 (H1) A/Brisbane/10/07 (H3) B/Brisbane/60/08) and the pandemic (A/California/7/2009 (H1)) antigens with no statistical difference between groups. 2010/2011: RA and SLE patients under treatment with DMARDS and HC fullfilled all the 3 immunogenity criteria, while RA under treatment with biological agents only 1 for A/Perth/16/09 (H3) and 2 for A/California/7/2009 (H1) and B/Brisbane/60/08. Increase in GMT versus H1(p 0.008) and H3 (p 0.046) was statistically different between RA on biological and HC and versus H1 (p 0.034) and B (p 0.003) between RA on biological and RA on DMARDS in subjects immunized only with influenza. Among HC and RA patients under treatment with DMARDS immunized also with pneumococcal vaccine no response was observed vs H3 compared to the complete response in subjects immunized with only influenza (HC p 0.034) No significant difference in vaccine response has been observed among the different groups of biological agents (Etanercept, Infliximab, adalimumab, abatacept) The cohort follow-up revealed increase in GMT and seroprotection rate for A but not for B antigens. Cell-mediated immunity An increase in Tregs, activated cytokine-producing cells, T naïve and CM subsets and a decrease in T EM and TD lymphocytes, 30 days after vaccination, was observed both in patients and controls. In vitro studies showed that the presence of the polysaccharide vaccine inhibits specific and aspecific cellular immune response in a dose-dependent manner. Conclusion Response to seasonal influenza vaccination in RA and SLE patients under treatment with DMARDS is comparable to HC. The suboptimal response in the first and third seasons both in RA patients under treatment with biological agents and HC could be partially due to the simultaneous pneumococcal vaccination. Adjuvanted influenza vaccine looks to be safe and able to achieve strong immunogenicity, comparable to HC, even in this group of patients. The increase at T1 in activated T cells reflects the predominant implication of Th1 response to vaccination

A simplified genomic profiling approach predicts outcome in metastatic colorectal cancer

The response of metastatic colorectal cancer (mCRC) to the first-line conventional combination therapy is highly variable, reflecting the elevated heterogeneity of the disease. The genetic alterations underlying this heterogeneity have been thoroughly characterized through omic approaches requiring elevated efforts and costs. In order to translate the knowledge of CRC molecular heterogeneity into a practical clinical approach, we utilized a simplified Next Generation Sequencing (NGS) based platform to screen a cohort of 77 patients treated with first-line conventional therapy. Samples were sequenced using a panel of hotspots and targeted regions of 22 genes commonly involved in CRC. This revealed 51 patients carrying actionable gene mutations, 22 of which carried druggable alterations. These mutations were frequently associated with additional genetic alterations. To take into account this molecular complexity and assisted by an unbiased bioinformatic analysis, we defined three subgroups of patients carrying distinct molecular patterns. We demonstrated these three molecular subgroups are associated with a different response to first-line conventional combination therapies. The best outcome was achieved in patients exclusively carrying mutations on TP53 and/or RAS genes. By contrast, in patients carrying mutations in any of the other genes, alone or associated with mutations of TP53/RAS, the expected response is much worse compared to patients with exclusive TP53/RAS mutations. Additionally, our data indicate that the standard approach has limited efficacy in patients without any mutations in the genes included in the panel. In conclusion, we identified a reliable and easy-to-use approach for a simplified molecular-based stratification of mCRC patients that predicts the efficacy of the first-line conventional combination therapy

Clinical Multigene Panel Sequencing Identifies Distinct Mutational Association Patterns in Metastatic Colorectal Cancer

Extensive molecular characterization of human colorectal cancer (CRC) via Next Generation Sequencing (NGS) indicated that genetic or epigenetic dysregulation of a relevant, but limited, number of molecular pathways typically occurs in this tumor. The molecular picture of the disease is significantly complicated by the frequent occurrence of individually rare genetic aberrations, which expand tumor heterogeneity. Inter- and intratumor molecular heterogeneity is very likely responsible for the remarkable individual variability in the response to conventional and target-driven first-line therapies, in metastatic CRC (mCRC) patients, whose median overall survival remains unsatisfactory. Implementation of an extensive molecular characterization of mCRC in the clinical routine does not yet appear feasible on a large scale, while multigene panel sequencing of most commonly mutated oncogene/oncosuppressor hotspots is more easily achievable. Here, we report that clinical multigene panel sequencing performed for anti-EGFR therapy predictive purposes in 639 formalin-fixed paraffin-embedded (FFPE) mCRC specimens revealed previously unknown pairwise mutation associations and a high proportion of cases carrying actionable gene mutations. Most importantly, a simple principal component analysis directed the delineation of a new molecular stratification of mCRC patients in eight groups characterized by non-random, specific mutational association patterns (MAPs), aggregating samples with similar biology. These data were validated on a The Cancer Genome Atlas (TCGA) CRC dataset. The proposed stratification may provide great opportunities to direct more informed therapeutic decisions in the majority of mCRC cases

Induzione di anticorpi antinucleo in pazienti con artrite reumatoide trattati con etanercept:analisi preliminare sulle cellule T regolatorie

comunicazione oral

Safety and immunogenicity of co-administered MF59-adjuvanted 2009 pandemic and plain 2009-10 seasonal influenza vaccines in rheumatoid arthritis patients on biologicals

Rheumatoid arthritis (RA) patients under immunosuppressive therapy are particularly susceptible to infections, mainly of the respiratory tract, thus vaccination may represent a strategy to reduce their incidence in this vulnerable population. In the 2009-10 influenza season, the safety and immunogenicity of co-administered non-adjuvanted seasonal and MF59-adjuvanted pandemic influenza vaccines were evaluated in this study in 30 RA patients under therapy with anti-tumour necrosis factor (TNF)-α agents or Abatacept and in 13 healthy controls (HC). Patients and HC underwent clinical and laboratory evaluation before (T0), 1 (T1) and 6 months (T2) after vaccinations. No severe adverse reactions, but a significant increase in total mild side effects in patients versusHC were observed. Both influenza vaccines fulfilled the three criteria of the Committee for Proprietary Medicinal Products (CPMP). Seroconversion rate for any viral strain in patients and HC was, respectively, 68 versus 45 for H1-A/Brisbane/59/07, 72 versus 81 for H3-A/Brisbane/10/07, 68 versus 54 for B/Brisbane/60/08 and 81 versus 54 for A/California/7/2009. A slight increase in activated interferon (IFN)-γ-, TNF-α- or interleukin (IL)-17A-secreting T cells at T1 compared to T0, followed by a reduction at T2 in both patients and HC, was registered. In conclusion, simultaneous administration of adjuvanted pandemic and non-adjuvanted seasonal influenza vaccines is safe and highly immunogenic. The largely overlapping results between patients and HC, in terms of antibody response and cytokine-producing T cells, may represent further evidence for vaccine safety and immunogenicity in RA patients on biological

Influenza vaccine administration in rheumatoid arthritis patients under treatment with TNF alpha blockers: Safety and immunogenicity

Twenty-eight patients with low-moderate, stable rheumatoid arthritis (RA), under treatment with tumor necrosis factor (TNF) alpha blockers, were immunized at least once with non-adjuvanted trivalent influenza vaccine during three consecutive influenza seasons. Antibodies toward A influenza antigens significantly increased and reached protective levels, still detectable 6 months after vaccination, both in RA patients and healthy controls. Response to B antigen instead was only observed from the second year for healthy controls and in the third year for patients. No significant difference in disease activity and anti-nuclear antibodies was observed as a consequence of vaccine administration, whereas T regulatory cells showed a significant increase 30 days after immunization in RA patients. This study confirms safety of influenza vaccine administration in RA patients treated with TNFalpha blockers. The cohort follow-up revealed the overcoming of poor B vaccine antigen immunogenicity via repeated vaccinations. Finally, protective antibody response was still observed 6 months after vaccination. Copyright 2009 Elsevier Inc. All rights reserved

Lymphocyte subsets are influenced by positivity levels in healthy subjects before and after mild acute stress

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

Autologous non-myeloablative haemopoietic stem cell transplantation in relapsing-remitting multiple sclerosis: a phase I/II study

Background Autologous non-myeloablative haemopoietic stem cell transplantation is a method to deliver intense immune suppression. We evaluated the safety and clinical outcome of autologous non-myeloablative haemopoietic stem cell transplantation in patients with retapsing-remitting multiple sclerosis (MS) who had not responded to treatment with interferon beta. Methods Eligible patients had relapsing-remitting MS, attended Northwestern Memorial Hospital, and despite treatment with interferon beta had had two corticosteroid-treated relapses within the previous 12 months, or one relapse and gadolinium-enhancing lesions seen on MRI and separate from the relapse. Peripheral blood haemopoietic stem cells were mobilised with 2 g per m(2) cyclophosphamide and 10 mu g per kg per day filgrastim. The conditioning regimen for the haemopoietic stem cells was 200 mg per kg cyclophosphamide and either 20 mg alemtuzumab or 6 mg per kg rabbit antithymocyte globulin. Primary outcomes were progression-free survival and reversal of neurological disability at 3 years post-transplantation. We also sought to investigate the safety and tolerability of autologous non-myeloablative haemopoietic stem cell transplantation. Findings Between January 2003, and February, 2005, 21 patients were treated. Engraftment of white blood cells and platelets was on median day 9 (range day 8-11) and patients were discharged from hospital on mean day 11 (range day 8-13). One patient had diarrhoea due to Clostridium difficile and two patients had dermatomal zoster. Two of the 17 patients receiving alemtuzumab developed late immune thrombocytopenic purpura that remitted with standard therapy. 17 of 21 patients (81%) improved by at least 1 point on the Kurtzke expanded disability status scale (EDSS), and five patients (24%) relapsed but achieved remission after further immunosuppression. After a mean of 37 months (range 24-48 months), all patients were free from progression (no deterioration in EDSS score), and 16 were free of relapses. Significant improvements were noted in neurological disability, as determined by EDSS score (p<0.0001), neurological rating scale score (p=0.0001), paced auditory serial addition test (p=0.014), 25-foot walk (p<0.0001), and quality of life, as measured with the short form-36 (SF-36) questionnaire (p<0.0001). Interpretation Non-myeloablative autologous haemopoietic stem cell transplantation in patients with relapsing-remitting MS reverses neurological deficits, but these results need to be confirmed in a randomised trial.Division of ImmunotherapyNorthwestern Universit