The role of the Notch pathway in the pathogenesis of systemic sclerosis: clinical implications.

INTRODUCTION: Systemic sclerosis (SSc) is a chronic debilitating disease characterized by vascular insufficiency, widespread fibrosis and immune activation. Current understanding of its pathophysiology remains incomplete, which translates into inefficient therapies. Notch signaling is a central player in the development of physiological and pathological fibrosis not only in general but also in the context of SSc and is most likely involved in the vascular dysfunction that characterizes the disease. AREAS COVERED: This review explores the role of the Notch pathway in the pathophysiology of SSc and the potential implications for the diagnosis, evaluation, and management of this yet incurable disease. EXPERT OPINION: Although major issues still exist about the comprehension of SSc and the design of effective treatments, the knowledge of the role of the Notch pathway in fibrogenesis and vascular biology has shed light and enthusiasm over the field. Drugs that target components of Notch signaling are currently in development including already some in clinical trials. As such, Notch may become a very important topic in the near future (considering both the pathophysiology and treatment perspectives), not only in the context of SSc but also in the vascular-dependent fibrotic processes present in a multitude of diseases.

Changes in Iron Metabolism Induced by Anti-Interleukin-6 Receptor Monoclonal Antibody are Associated with an Increased Risk of Infection.

(1) Background: Treatment of patients with rheumatoid arthritis (RA) with an anti-IL-6 receptor (anti-IL-6R) monoclonal antibody (tocilizumab) has been found to influence iron metabolism. The objective of the present study was to ascertain whether changes in iron metabolism induced by anti-IL-6R biologic therapy were independently associated with an increased infection risk. (2) Methods: A prospective longitudinal study of patients with RA treated with tocilizumab was conducted. RA patients treated with an antitumor necrosis factor α monoclonal antibody were also included as a control group. The primary outcome was occurrence of infection during the first 24 months of biologic therapy. (3) Results: A total of 15 patients were included, with a mean age of 51.0 ± 4,1 and 73.3% (n = 11) female. A multivariate survival regression model, adjusted for confounding factors, was fitted for each of the iron metabolism variables. Hazard ratios for being above the median of each parameter was considered. Transferrin saturation above the median value (>32.1%) was associated with a higher infection risk (HR 4.3; 95%CI 1.0-19.69; p = 0.05). Similarly, although non-significantly, higher serum iron was strongly associated with infection occurrence. (4) Conclusions: This study identified a probable association between infection risk and higher serum iron and transferrin saturation in patients with RA on anti-IL-6R biologic therapy. We suggest that both these parameters should be considered relevant contributing factors for infection occurrence in patients on anti-IL-6R therapy.