Persistence and Adherence during the First Six Months of Tocilizumab Treatment Among Rheumatoid Arthritis Patients in Routine Clinical Practice in Greece. Results from the Single Arm REMISSION II Study (NCT01649817).

OBJECTIVE/AIM: One of the most important factors that affect a treatment's performance in rheumatoid arthritis (RA) is adherence to medications. According to literature, there are several reasons for non-adherence in RA patients with some of them being related to a specific patient profile of the study population. In this study, we investigated persistence to intravenous tocilizumab (TCZ) therapy in RA during routine clinical practice in Greece and identified causes for non-adherence. METHODS: 183 RA patients who mostly attended private practice Rheumatologists and received intravenous TCZ treatment at a schedule of 1 infusion per 4-weeks in the first 6 months were recorded retrospectively. RESULTS: Persistence estimated rate to TCZ therapy was 92.0% for patients that received 6 infusions and 83.4% for patients that received 7 infusions of TCZ. Potential factors that influence persistence to therapy were the occurrence of adverse events and response to the therapy. The main reasons for non-adherence to TCZ therapy were non-medically related with the most common being drug supply issues. The 6-month mean change from baseline in DAS28-ESR after initiation of TCZ therapy was -1.3, and the mean CDAI dropped from 29.6 at baseline to 16.7 at 6 months. Good/Moderate response was achieved by 89.1% of patients and remission by 23.5%. The safety profile was similar to that observed in other TCZ trials with the most common being infections, hematologic manifestations and musculoskeletal disorders. CONCLUSION: Overall, persistence to therapy appeared to be high in the rheumatology private practice setting and non-adherence to the TCZ treatment schedule is attributed mainly to non-medical reasons.

Bmp7 regulates the survival, proliferation, and neurogenic properties of neural progenitor cells during corticogenesis in the mouse.

Bone morphogenetic proteins (BMPs) are considered important regulators of neural development. However, results mainly from a wide set of in vitro gain-of-function experiments are conflicting since these show that BMPs can act either as inhibitors or promoters of neurogenesis. Here, we report a specific and non-redundant role for BMP7 in cortical neurogenesis in vivo using knockout mice. Bmp7 is produced in regions adjacent to the developing cortex; the hem, meninges, and choroid plexus, and can be detected in the cerebrospinal fluid. Bmp7 deletion results in reduced cortical thickening, impaired neurogenesis, and loss of radial glia attachment to the meninges. Subsequent in vitro analyses of E14.5 cortical cells revealed that lack of Bmp7 affects neural progenitor cells, evidenced by their reduced proliferation, survival and self-renewal capacity. Addition of BMP7 was able to rescue these proliferation and survival defects. In addition, at the developmental stage E14.5 Bmp7 was also required to maintain Ngn2 expression in the subventricular zone. These data demonstrate a novel role for Bmp7 in the embryonic mouse cortex: Bmp7 nurtures radial glia cells and regulates fundamental properties of neural progenitor cells that subsequently affect Ngn2-dependent neurogenesis.

Compartmentalization of bone morphogenetic proteins and their antagonists in lymphoid progenitors and supporting microenvironments and functional implications.

Bone morphogenetic protein (BMP) signalling regulates lymphopoiesis in bone marrow and thymus via the interaction of haemato-lymphoid progenitors with the stroma microenvironment. Despite increasing functional evidence for the role of BMP signalling in lymphopoiesis, little is known of the spatial distribution of BMP/BMP antagonists in the thymus and of how BMP signals exert specific functions in developing lymphocytes. We analysed expression of BMP/BMP antagonists in the thymus and bone marrow and determined the topology of BMP/BMP antagonist expression using lacZ reporter mice. Bmp4, Bmp7, Gremlin and Twisted gastrulation (Twsg1) are all expressed in the thymus and expression was clearly different for each gene investigated. Expression was seen both in cortical and medullary regions suggesting that BMP signals regulate all stages of T-cell development. Two genes in particular, Bmp7 and Twsg1, were dynamically expressed in developing T and B lymphocytes. Their conditional ablation in all haematopoietic cells surprisingly did not affect the steady state of B-cell and T-cell development. This indicates that both lymphoid cell-derived BMP7 and TWSG1 are dispensable for normal lymphopoiesis and that bone-marrow stroma-derived TWSG1 is responsible for the lymphoid defects observed in Twsg1 null mice. In summary our data demonstrate a complex network of lymphoid and stroma derived BMP signals involved in the orchestration of lymphopoiesis in both bone marrow and thymus.

Involvement of twisted gastrulation in T cell-independent plasma cell production.

Bone morphogenetic protein (BMP) signaling is increasingly implicated in immune cell differentiation and function; however, direct in vivo evidence for such a role is still missing. In this article, we report that Twisted gastrulation (TWSG1), an extracellular regulator of BMP signaling, is expressed in activated B cells and regulates T-independent B cell responses in the mouse. Twsg1-deficient B cells mount stronger T-independent type 2 responses reflected as increased IgM levels and numbers of Ag-specific IgM-secreting cells. BCR stimulation of Twsg1-deficient B cells results in hyperproliferation, hyperresponsiveness, and decreased apoptosis, whereas TLR stimulation results in hyperproliferation and increased IgG3 production. These changes are reflected on the molecular level by increased transcription of Bcl-6, Pax5, and the BMP-responsive gene Id-2. The TWSG1 effects on B cells appear to be cell intrinsic, suggesting that Twsg1 expression in B cells serves to interpret BMP signals on a per-cell basis. In summary, our observations on the role of TWSG1 in B cell function is opening new paths toward the exploration of the role of BMP signaling in immunological processes.

Generation and functional characterization of mice with a conditional BMP7 allele.

Bone Morphogenetic Proteins (BMPs) play multiple and important roles in embryonic development as well as in homeostasis and tissue repair in the adult. Bmp7 has been implicated in developmental disorders and in a variety of diseases, but functional studies to elucidate its role so far have been hampered, since mice deficient in BMP7 die around or just after birth. To facilitate such studies, we generated mice in which the Bmp7 gene has been rendered conditional-null by flanking its first coding exon with loxP sites. To this end, we adapted the two-loxP site strategy to Bacterial Homologous Recombination to create a Bacterial Artificial Chromosome-based vector for direct targeting in mouse embryonic stem cells. Functional analysis showed that in vivo, the conditional-null Bmp7(flx/flx) mice are phenotypically wild type, whereas post Cre-mediated recombination, the resulting Bmp7(delta/delta) mice are phenotypically null. Thus, this study validates the usefulness of the Bmp7(flx/flx) mouse which in turn should empower in vivo studies aimed at elucidating the roles of Bmp7 in postnatal development, homeostasis and disease.