Efficacité clinique et biologique du tocilizumab au cours de la maladie de Horton : à propos de trois observations et revue de la littérature

Introduction

Treatment of giant cell arteritis is based on prolonged corticosteroid therapy but adverse side effects are common especially in the elderly.

Case reports

We report three patients with giant cell vasculitis treated by tocilizumab, an interleukin-6 receptor antibody, owing to resistance or intolerance to corticosteroid therapy. A favorable outcome was rapidly observed both on clinical and biological data allowing a corticoid therapy sparing.

Conclusion

Tocilizumab is a promising treatment of giant cell arteritis but controlled trials are needed to confirm its efficacy.     

Genetic ablation of delta opioid receptors in nociceptive sensory neurons increases chronic pain and abolishes opioid analgesia

Opioid receptors are major actors in pain control and are broadly distributed throughout the nervous system. A major challenge in pain research is the identification of key opioid receptor populations within nociceptive pathways, which control physiological and pathological pain. In particular, the respective contribution of peripheral vs. central receptors remains unclear, and it has not been addressed by genetic approaches. To investigate the contribution of peripheral delta opioid receptors in pain control, we created conditional knockout mice where delta receptors are deleted specifically in peripheral Na_V1.8-positive primary nociceptive neurons. Mutant mice showed normal pain responses to acute heat and to mechanical and formalin stimuli. In contrast, mutant animals showed a remarkable increase of mechanical allodynia under both inflammatory pain induced by complete Freund adjuvant and neuropathic pain induced by partial sciatic nerve ligation. In these 2 models, heat hyperalgesia was virtually unchanged. SNC80, a delta agonist administered either systemically (complete Freund adjuvant and sciatic nerve ligation) or into a paw (sciatic nerve ligation), reduced thermal hyperalgesia and mechanical allodynia in control mice. However, these analgesic effects were absent in conditional mutant mice. In conclusion, this study reveals the existence of delta opioid receptor-mediated mechanisms, which operate at the level of Na_V1.8-positive nociceptive neurons. Delta receptors in these neurons tonically inhibit mechanical hypersensitivity in both inflammatory and neuropathic pain, and they are essential to mediate delta opioid analgesia under conditions of persistent pain. This delta receptor population represents a feasible therapeutic target to alleviate chronic pain while avoiding adverse central effects.     

Congenital toxoplasmosis: randomised comparison of strategies for retinochoroiditis prevention

In France, children with confirmed congenital toxoplasmosis receive a treatment for a period of 12 to 24 months. Such prolonged treatment may generate potentially severe risks, in particular hematologic and cutaneous. Our objective is to compare the effectiveness of two therapeutic strategies on the prevention of retinochoroiditis by a randomized, non-inferiority, open-label, parallel study including 486 children, 3 to 6 months of age with a non-severe form of congenital toxoplasmosis. Following randomization, pyrimethamine-sulphonamide treatment is initiated for a period of three months, followed by a treatment with Fansidar(?) for 9 months, or therapeutic abstention. Follow-up visits during a two-year period will include an examination of the eye, a blood test, and questionnaires to evaluate the children's quality of life and their parents' anxiety. Confirming the non-inferiority of the effectiveness of a short-term treatment will improve the quality of life of parents and children.     

Activation of recombinant alphaIIbbeta3 expressed in Chinese hamster ovary cells exposes different binding sites for fibrinogen or von Willebrand factor: evidence using monoclonal antibodies to alphaIIbbeta3

We have investigated the interaction of von Willebrand factor (VWF) and fibrinogen (Fg) with recombinant integrin alphaIIbbeta3 expressed in Chinese hamster ovary (CHO) cells either in its native conformation or following partial reduction by dithiothreitol (DTT). We found that DTT-treated cells aggregated in the presence of soluble VWF as well as Fg, whereas non-treated cells did not. Furthermore, we demonstrated that DTT was required to specifically induce alphaIIbbeta3-dependent cell adhesion to immobilized VWF, while Fg-dependent cell adhesion occurred independently of the activation state of alphaIIbbeta3. By comparing the effects of two potent platelet alphaIIbbeta3 inhibitors, monoclonal antibodies (mAbs) AP2 and 10E5, we highlighted the different blocking properties of these mAbs on VWF or Fg binding to activated alphaIIbbeta3. In particular, AP2 prevented VWF-dependent but not Fg-dependent CHO cell aggregation. Furthermore, AP2 inhibited cell adhesion to VWF, but had no effect on adhesion to Fg. In contrast to this distinct effect of AP2 towards these two ligands, mAb 10E5 inhibited activated alphaIIbbeta3-dependent aggregation completely and adhesion partially, whether in the presence of Fg or VWF. These data provide evidence that interaction of VWF and Fg with DTT-activated alphaIIbbeta3 relies on distinct contact sites exposed on the activated receptor that can be selectively blocked by monoclonal antibodies.     

Acitretin-induced pneumonia: an underestimated complication of treatment of psoriasis

INTRODUCTION: Retinoids are known to induce side effects which can be severe. Alveolar and interstitial pneumonia of uncertain pathogenesis can rarely occur when retinoid are used among patients with psoriasis. EXEGESIS: We report an observation of acute respiratory distress beginning 26 days after introduction of acitretin, a second-generation retinoid. Treatment withdrawal and corticotherapy allow a spectacular amelioration of respiratory conditions. CONCLUSION: Pneumonia induced by retinoid must be known as a side effect of treatment of psoriasis.     

Receptor protein tyrosine phosphatase beta/zeta is a functional binding partner for vascular endothelial growth factor

Background

Receptor protein tyrosine phosphatase beta/zeta (RPTPβ/ζ) is a chondroitin sulphate (CS) transmembrane protein tyrosine phosphatase and is a receptor for pleiotrophin (PTN). RPTPβ/ζ interacts with α_νβ₃ on the cell surface and upon binding of PTN leads to c-Src dephosphorylation at Tyr530, β₃ Tyr773 phosphorylation, cell surface nucleolin (NCL) localization and stimulation of cell migration. c-Src-mediated β₃ Tyr773 phosphorylation is also observed after vascular endothelial growth factor 165 (VEGF₁₆₅) stimulation of endothelial cells and is essential for VEGF receptor type 2 (VEGFR2) - α_νβ₃ integrin association and subsequent signaling. In the present work, we studied whether RPTPβ/ζ mediates angiogenic actions of VEGF.

Methods

Human umbilical vein endothelial, human glioma U87MG and stably transfected Chinese hamster ovary cells expressing different β₃ subunits were used. Protein-protein interactions were studied by a combination of immunoprecipitation/Western blot, immunofluorescence and proximity ligation assays, properly quantified as needed. RPTPβ/ζ expression was down-regulated using small interference RNA technology. Migration assays were performed in 24-well microchemotaxis chambers, using uncoated polycarbonate membranes with 8 μm pores.

Results

RPTPβ/ζ mediates VEGF₁₆₅-induced c-Src-dependent β₃ Tyr773 phosphorylation, which is required for VEGFR2-α_νβ₃ interaction and the downstream activation of phosphatidylinositol 3-kinase (PI3K) and cell surface NCL localization. RPTPβ/ζ directly interacts with VEGF₁₆₅, and this interaction is not affected by bevacizumab, while it is interrupted by both CS-E and PTN. Down-regulation of RPTPβ/ζ by siRNA or administration of exogenous CS-E abolishes VEGF₁₆₅-induced endothelial cell migration, while PTN inhibits the migratory effect of VEGF₁₆₅ to the levels of its own effect.

Conclusions

These data identify RPTPβ/ζ as a cell membrane binding partner for VEGF that regulates angiogenic functions of endothelial cells and suggest that it warrants further validation as a potential target for development of additive or alternative anti-VEGF therapies.

Electronic supplementary material

The online version of this article (doi:10.1186/s12943-015-0287-3) contains supplementary material, which is available to authorized users.