Randomized phase I trial of antigen-specific tolerizing immunotherapy with peptide/calcitriol liposomes in ACPA+ rheumatoid arthritis

BACKGROUND. Antigen-specific regulation of autoimmune disease is a major goal. In seropositive rheumatoid arthritis (RA), T cell help to autoreactive B cells matures the citrullinated (Cit) antigen-specific immune response, generating RA-specific V domain glycosylated anti-Cit protein antibodies (ACPA VDG) before arthritis onset. Low or escalating antigen administration under “sub-immunogenic” conditions favors tolerance. We explored safety, pharmacokinetics, and immunological and clinical effects of s.c. DEN-181, comprising liposomes encapsulating self-peptide collagen II259-273 (CII) and NF-κB inhibitor 1,25-dihydroxycholecalciferol. METHODS. A double-blind, placebo-controlled, exploratory, single-ascending-dose, phase I trial assessed the impact of low, medium, and high DEN-181 doses on peripheral blood CII-specific and bystander Cit64vimentin59-71–specific (Cit-Vim–specific) autoreactive T cell responses, cytokines, and ACPA in 17 HLA-DRB1*04:01+ or *01:01+ ACPA+ RA patients on methotrexate. RESULTS. DEN-181 was well tolerated. Relative to placebo and normalized to baseline values, Cit-Vim–specific T cells decreased in patients administered medium and high doses of DEN-181. Relative to placebo, percentage of CII-specific programmed cell death 1+ T cells increased within 28 days of DEN-181. Exploratory analysis in DEN-181–treated patients suggested improved RA disease activity was associated with expansion of CII-specific and Cit-Vim–specific T cells; reduction in ACPA VDG, memory B cells, and inflammatory myeloid populations; and enrichment in CCR7+ and naive T cells. Single-cell sequencing identified T cell transcripts associated with tolerogenic TCR signaling and exhaustion after low or medium doses of DEN-181. CONCLUSION. The safety and immunomodulatory activity of low/medium DEN-181 doses provide rationale to further assess antigen-specific immunomodulatory therapy in ACPA+ RA

Revising dating estimates and the antiquity of eusociality in termites using the fossilized birth-death process

International audienceDeciphering the timing and tempo of lineage diversification of organisms has greatly benefited from advances in Bayesian phylogenetic analyses using morphological data. Those advances, however, have not been used for termites despite a rich fossil record. Here, we estimate divergence times for living and fossil termites using the fossilized birth–death (FBD) process on a previously published morphological matrix expanded with two new fossils that we describe (see Appendices 1 & 2). Those fossils, based on soldier specimens, are the ‘mid’-Cretaceous mastotermitid Milesitermesengeligen. et sp. nov., and the Middle Eocene Reticulitermesgrimaldiisp. nov. The latter is the oldest occurrence of a Rhinotermitidae soldier and the first termite soldier described from Baltic amber. Our dating estimates provide new stem- and crown-ages for termites, suggesting older ages than previously thought for several lineages. Importantly, crown-Isoptera—and therefore eusociality—may have arisen ~200 Ma. We conclude with further directions to keep improving our understanding of the timing of differentiation in termites.Page 2 of 77Systematic Entomolog

II Consenso Colombiano para el Manejo de la Osteoporosis Posmenopáusica

The Colombian Osteoporosis and Mineral Metabolism Association met in early 2017 to update the Colombian Consensus on Osteoporosis. This was first issued in 2005, and is seen as a necessary step in view of the underdiagnosed status of this disease, and the expected impact of population ageing. A technical team was formed with specialists with long experience across multiple disciplines, who were assigned to four working groups: definitions and epidemiology, diagnosis, pharmacological treatment, and non-pharmacological treatment. After a scientific literature review and a series of meetings, the definitions and recommendations are summarised in this article. © 2018 Asociación Colombiana de Reumatologí

II Consenso Colombiano para el Manejo de la Osteoporosis Posmenopáusica

The Colombian Osteoporosis and Mineral Metabolism Association met in early 2017 to update the Colombian Consensus on Osteoporosis. This was first issued in 2005, and is seen as a necessary step in view of the underdiagnosed status of this disease, and the expected impact of population ageing. A technical team was formed with specialists with long experience across multiple disciplines, who were assigned to four working groups: definitions and epidemiology, diagnosis, pharmacological treatment, and non-pharmacological treatment. After a scientific literature review and a series of meetings, the definitions and recommendations are summarised in this article. © 2018 Asociación Colombiana de Reumatologí