The Real-World Effectiveness and Safety of Ustekinumab in the Treatment of Crohn's Disease: Results From the SUCCESS Consortium.

INTRODUCTION: We evaluated the real-world effectiveness and safety of ustekinumab (UST) in patients with Crohn's disease (CD). METHODS: This study used a retrospective, multicenter, multinational consortium of UST-treated CD patients. Data included patient demographics, disease phenotype, disease activity, treatment history, and concomitant medications. Cumulative rates of clinical, steroid-free, endoscopic, and radiographic remissions were assessed using time-to-event analysis, and clinical predictors were assessed by using multivariate Cox proportional hazard analyses. Serious infections and adverse events were defined as those requiring hospitalization or treatment discontinuation. RESULTS: A total of 1,113 patients (51.8% female, 90% prior antitumor necrosis factor exposure) were included, with a median follow-up of 386 days. Cumulative rates of clinical, steroid-free, endoscopic, and radiographic remissions at 12 months were 40%, 32%, 39%, and 30%, respectively. Biologic-naive patients achieved significantly higher rates of clinical and endoscopic remissions at 63% and 55%, respectively. On multivariable analyses, prior antitumor necrosis factor (hazard ratio, 0.72; 95% confidence interval, 0.49-0.99) and vedolizumab exposure (hazard ratio, 0.65; 95% confidence interval, 0.48-0.88) were independently associated with lower likelihoods of achieving endoscopic remission. In patients who experienced loss of remission, 77 of 102 (75%) underwent dose optimization, and 44 of 77 (57%) achieved clinical response. An additional 152 of 681 patients (22.3%) were dose-optimized because of primary nonresponse incomplete response to UST, of whom 40.1% (61 of 152) responded. Serious infections occurred in 3.4% of patients while other noninfectious adverse events (lymphoma [n = 1], arthralgia [n = 6], rash [n = 6], headache [n = 3], hepatitis [n = 3], hair loss [n = 3], neuropathy [n = 1], and vasculitis [n = 1]) occurred in 2.4% of patients. DISCUSSION: UST represents a safe and effective treatment option for CD, with 40% of patients from a highly refractory cohort achieving clinical remission by 12 months. The greatest treatment effect of UST was seen in biologic-naive patients, and dose escalation may recapture clinical response.

Crohn's Disease Mortality and Ambient Air Pollution in New York City.

BACKGROUND: The worldwide increase in Crohn's disease (CD) has accelerated alongside rising urbanization and accompanying decline in air quality. Air pollution affects epithelial cell function, modulates immune responses, and changes the gut microbiome composition. In epidemiologic studies, ambient air pollution has a demonstrated relationship with incident CD and hospitalizations. However, no data exist on the association of CD-related death and air pollution. METHODS: We conducted an ecologic study comparing the number of CD-related deaths of individuals residing in given zip codes, with the level of air pollution from nitric oxide, nitrogen dioxide, sulfur dioxide (SO2), and fine particulate matter. Air pollution was measured by the New York Community Air Survey. We conducted Pearson correlations and a Poisson regression with robust standard errors. Each pollution component was modeled separately. RESULTS: There was a higher risk of CD-related death in zip codes with higher levels of SO2 (incidence rate ratio [IRR], 1.16; 95% confidence interval [CI], 1.06-1.27). Zip codes with higher percentage of Black or Latinx residents were associated with lower CD-related death rates in the SO2 model (IRR, 0.58; 95% CI, 0.35-0.98; and IRR, 0.13; 95% CI, 0.05-0.30, respectively). There was no significant association of either population density or area-based income with the CD-related death rate. CONCLUSIONS: In New York City from 1993 to 2010, CD-related death rates were higher among individuals from neighborhoods with higher levels of SO2 but were not associated with levels of nitric oxide, nitrogen dioxide, and fine particulate matter. These findings raise an important and timely public health issue regarding exposure of CD patients to environmental SO2, warranting further exploration.

Ecologic study comparing the number of Crohn's disease related deaths of individuals residing in given zip codes within New York City, with levels of air pollution from nitric oxide, nitrogen dioxide, sulfur dioxide, and fine particulate matter.

p67/MetAP2 suppresses K-RasV12-mediated transformation of NIH3T3 mouse fibroblasts in culture and in athymic mice.

In many tumor cells, the activation and activity of extracellular signal-regulated kinases (ERK1/2) are very high because of the constitutive activation of the Ras-mediated signaling pathway. Here, we ectopically expressed the human homologue of rat eukaryotic initiation factor 2-associated glycoprotein, p67/MetAP2, in EGF-treated mouse embryonic NIH3T3 fibroblasts and C2C12 myoblasts and NIH3T3 cell lines expressing the constitutively active form of MAP kinase kinase (MEK) to inhibit the activation and activity of ERK1/2 MAP kinases. In addition, we also ectopically expressed rat p67/MetAP2 in oncogenic Ras-induced transformed NIH3T3 fibroblasts and inhibited their transformed phenotype both in culture and in athymic nude mice possibly by inhibiting angiogenesis. This inhibition of ERK1/2 MAP kinases is due to the direct binding with rat p67/MetAP2, and this leads to the inhibition of activity of ERK1/2 MAP kinases both in vitro and in vivo. Furthermore, expression of p67/MetAP2 siRNA in both NIH3T3 fibroblasts and C2C12 myoblasts causes activation and activity of ERK1/2 MAP kinases. Our results thus suggest that ectopic expression of rat p67/MetAP2 in transformed cells can inhibit the tumorigenic phenotype by inhibiting the activation and activity of ERK1/2 MAP kinases and, thus, that p67/MetAP2 has tumor suppression activity.