Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease

Background: Experimental and clinical data suggest that reducing inflammation without affecting lipid levels may reduce the risk of cardiovascular disease. Yet, the inflammatory hypothesis of atherothrombosis has remained unproved. Methods: We conducted a randomized, double-blind trial of canakinumab, a therapeutic monoclonal antibody targeting interleukin-1β, involving 10,061 patients with previous myocardial infarction and a high-sensitivity C-reactive protein level of 2 mg or more per liter. The trial compared three doses of canakinumab (50 mg, 150 mg, and 300 mg, administered subcutaneously every 3 months) with placebo. The primary efficacy end point was nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. RESULTS: At 48 months, the median reduction from baseline in the high-sensitivity C-reactive protein level was 26 percentage points greater in the group that received the 50-mg dose of canakinumab, 37 percentage points greater in the 150-mg group, and 41 percentage points greater in the 300-mg group than in the placebo group. Canakinumab did not reduce lipid levels from baseline. At a median follow-up of 3.7 years, the incidence rate for the primary end point was 4.50 events per 100 person-years in the placebo group, 4.11 events per 100 person-years in the 50-mg group, 3.86 events per 100 person-years in the 150-mg group, and 3.90 events per 100 person-years in the 300-mg group. The hazard ratios as compared with placebo were as follows: in the 50-mg group, 0.93 (95% confidence interval [CI], 0.80 to 1.07; P = 0.30); in the 150-mg group, 0.85 (95% CI, 0.74 to 0.98; P = 0.021); and in the 300-mg group, 0.86 (95% CI, 0.75 to 0.99; P = 0.031). The 150-mg dose, but not the other doses, met the prespecified multiplicity-adjusted threshold for statistical significance for the primary end point and the secondary end point that additionally included hospitalization for unstable angina that led to urgent revascularization (hazard ratio vs. placebo, 0.83; 95% CI, 0.73 to 0.95; P = 0.005). Canakinumab was associated with a higher incidence of fatal infection than was placebo. There was no significant difference in all-cause mortality (hazard ratio for all canakinumab doses vs. placebo, 0.94; 95% CI, 0.83 to 1.06; P = 0.31). Conclusions: Antiinflammatory therapy targeting the interleukin-1β innate immunity pathway with canakinumab at a dose of 150 mg every 3 months led to a significantly lower rate of recurrent cardiovascular events than placebo, independent of lipid-level lowering. (Funded by Novartis; CANTOS ClinicalTrials.gov number, NCT01327846.

The Legume–Rhizobia Symbiosis

The symbiotic nitrogen fixation (SNF) with legumes is the primary source of biologically fixed nitrogen for agricultural system. It is performed by a group of bacteria commonly called rhizobia. It is characterized by a host preference, and the differences among symbioses between rhizobial strains and legume genotypes are related to infection, nodule development and effectiveness in N2 fixation. The interaction between a rhizobia and the legume is mediated by a lipochitin oligosaccharide secreted by the rhizobia, and called “Nod factor”. It is recognized by transmembrane receptors on the root-hair cells of the legume. It can regulate the nodule organogenesis by inducing changes in the cytokinin balance of the root, during nodule initiation. N2 fixation in legume nodules is catalyzed by the nitrogenase enzyme depending upon the photosynthate supply, the O2 concentration, and the fixed-N export. Among environmental factors that influence the SNF, the temperature is essential for nodule formation; the salinity and drought decrease the nodule permeability to O2 and the photosynthate supply to the nodule, the phosphorus deficiency inhibits the nodule development and the total N2 fixation. Rhizobia strains differ in their efficiency in N2 fixation with host legume. There is evidence of genotypic variability for SNF at different levels of available P which show a possibility of selecting cultivars able to support biological N2 fixation under low P soils