Effect of TNFα blockade on UVB-induced inflammatory cell migration and collagen loss in mice.

UVB irradiation induces pro-inflammatory cytokines including interleukin-1 (IL-1) and tumor necrosis factor-α (TNFα) in the skin. TNFα stimulates the chemotaxis of inflammatory cells to the skin. These cells secrete metalloproteinases (MMPs) and other enzymes that damage the cutaneous matrix. Therefore, blocking TNFα activity could be effective in preventing the influx of inflammatory cells and subsequent collagen degradation in the skin. In addition, TNFα downregulates procollagen mRNA, and thus blockade may be beneficial to production of type I collagen. Female C57BL/6 J mice were treated with etanercept (TNFα blocker, 4 mg/kg/day) for 4 days 1 h prior to UVB irradiation (100 mJ/cm2/day for 5 days). On the 5th day mice were sacrificed 3 h after UVB exposure. Blocking TNFα significantly inhibited UVB-induced recruitment of macrophages, mast cells, and neutrophils. UVB-irradiated mice skin contained more mature collagen compared to etanercept and UVB + etanercept-treated mice. Skin from UVB + etanercept-treated mice had more collagen fragments relative to UVB-irradiated mice. Procollagen protein was lower in UVB-irradiated and UVB + etanercept-treated mice. TNFα blockade decreased decorin and TGF-ß1 in UVB-irradiated mice compared to UVB alone. MMP13 was inhibited by etanercept in UVB-irradiated mice (p < 0.01). In conclusion, blockade of TNFα significantly decreased mature collagen in UVB-irradiated mice, while increasing collagen fragmentation and decreasing procollagen.

Direct-Acting Antiviral Therapy Not Associated With Recurrence of Hepatocellular Carcinoma in a Multicenter North American Cohort Study.

BACKGROUND & AIMS: There is controversy over the effects of direct-acting antiviral (DAA) therapies for hepatitis C virus (HCV) infection on hepatocellular carcinoma (HCC) recurrence and tumor aggressiveness. We compared HCC recurrence patterns between DAA-treated and untreated HCV-infected patients who had achieved a complete response to HCC treatment in a North American cohort. METHODS: We conducted a retrospective cohort study of patients with HCV-related HCC with a complete response to resection, local ablation, transarterial chemo- or radioembolization, or radiation therapy from January 2013 through December 2017 at 31 health systems throughout the United States and Canada. Cox regression was used to examine the association between DAA therapy and time to recurrence after a complete response, with DAA therapy analyzed as a time-varying exposure. We also estimated the association between DAA therapy and risk of early HCC recurrence (defined as 365 days after complete response). RESULTS: Of 793 patients with HCV-associated HCC, 304 (38.3%) received DAA therapy and 489 (61.7%) were untreated. HCC recurred in 128 DAA-treated patients (42.1%; early recurrence in 52 patients) and 288 untreated patients (58.9%; early recurrence in 227 patients). DAA therapy was not associated with HCC recurrence (hazard ratio 0.90, 95% confidence interval 0.70-1.16) or early HCC recurrence (hazard ratio 0.96, 95% confidence interval 0.70-1.34) after we adjusted for study site, age, sex, Child-Pugh score, α-fetoprotein level, tumor burden, and HCC treatment modality. In DAA-treated and untreated patients, most recurrences were within the Milan criteria (74.2% vs 78.8%; P = .23). A larger proportion of DAA-treated than untreated patients received potentially curative HCC therapy for recurrent HCC (32.0% vs 24.6%) and achieved a complete or partial response (45.3% vs 41.0%) but this did not achieve statistical significance. CONCLUSION: In a large cohort of North American patients with complete response to HCC treatment, DAA therapy was not associated with increased overall or early HCC recurrence. HCC recurrence patterns, including treatment response, were similar in DAA-treated and untreated patients.

Sustained Virological Response Is Associated with a Decreased Risk of Posttransplant Diabetes Mellitus in Liver Transplant Recipients with Hepatitis C-Related Liver Disease.

Posttransplant diabetes mellitus (PTDM), an increasingly recognized complication of solid organ transplantation, is associated with increased morbidity and mortality following liver transplantation (LT). Hepatitis C virus (HCV) infection is a consistent and modifiable risk factor for PTDM. Prior studies have demonstrated improvement in glucose metabolism following sustained virological response (SVR). However, the effect of SVR on the incidence of PTDM has not been previously investigated in a large cohort of LT recipients. We performed a single-center retrospective cohort study of LT recipients with HCV from January 1, 2010 to June 30, 2015 to compare the risk of sustained posttransplant diabetes mellitus (s-PTDM) prior to and following SVR. SVR was treated as a discrete time varying exposure. The s-PTDM was defined as de novo diabetes mellitus following LT of a >6-month duration. Univariate and multivariate Cox proportional hazards models were used to compare crude and adjusted time to s-PTDM prior to and following SVR. There were 256 eligible LT recipients analyzed. Median follow-up was 41.2 months. Overall, 31 (12.1%) and 178 (69.5%) patients achieved SVR prior to LT and following LT, respectively. During follow-up, 71 (27.7%) patients developed s-PTDM. The incidence of s-PTDM was greatest in the first year after LT. After adjustment for potential confounders, SVR was associated with a significantly reduced risk of s-PTDM (HR, 0.40; P = 0.048). In conclusion, eradication of HCV is independently associated with a reduced incidence of s-PTDM. This benefit appears to be most influenced by pre-LT SVR and persists throughout the post-LT period. Given the association between PTDM and posttransplant morbidity and mortality, these data provide another motivator for pre-LT or early post-LT treatment of HCV.

Advances in HCV and Cryoglobulinemic Vasculitis in the Era of DAAs: Are We at the End of the Road?

Hepatitis C Virus (HCV)-related Mixed Cryoglobulinemia (MC) is a unique condition with complex pathogenesis that involves HCV antigen-driven B-lymphocyte clonal proliferation and mutagenesis. Clinical spectrum of MC ranges from asymptomatic state to clinically-apparent vasculitis involving multiple organs. In the era of Direct-Acting Antiviral (DAA) therapy, patients with HCV-related MC achieve high rates of viral clearance that is commonly accompanied by an improvement in clinical symptoms as well as immunological profiles. Rituximab, either alone or in combination with DAA, has also been shown to be effective. Nevertheless, there have been limited and somewhat conflicting data, particularly over the long-term, regarding the rate and degree of clinical response of MC following DAA therapy. It appears that we have come quite a long way in the last decade with this condition. As with non-MC related HCV, undoubtedly long term outcome data will be forthcoming over the next few years. As we move forward successful therapy of HCV is not likely to be a challenge in contrast to access to therapy.

Neutrophil-to-Lymphocyte Ratio Associates Independently With Mortality in Hospitalized Patients With Cirrhosis.

BACKGROUND & AIMS: The neutrophil to lymphocyte ratio (NLR) is a biomarker of immune dysregulation in patients with cirrhosis and is inexpensive to measure. We investigated the association between NLR and mortality in hospitalized patients with cirrhosis at 4 liver transplant centers, controlling for severity of acute-on-chronic liver failure (ACLF). METHODS: We performed a retrospective study using data from the North American Consortium for the Study of End-stage Liver Disease on patients with index hospitalizations for cirrhosis from December 2011 through December 2016. We collected data on patient demographics, NLR, model for end-stage liver disease (MELD) scores, serum levels of Na, cirrhosis stages, infections, hepatocellular carcinomas, and ACLF severity (based on number of organ failures). Competing risk regression analysis evaluated mortality within 1 year after hospital discharge, accounting for competing events (liver transplant). RESULTS: At admission, the patients' mean age was 57 years, mean MELD score was 21, and mean serum level of Na was 134 mmol/L. Sixty-eight patients had no organ failure, 21 patients had 1 organ failures, 7 patients had 2 organ failures, 4 patients had 3 organ failures, and 1 patient had 4 organ failures; 36% of the patients had confirmed or suspected infections. In univariate models, risk of death associated with increasing NLR, up to a value of 8 (hazard ratio [HR]= 1.14; 95% CI, 1.07-1.20; P < .001), and NLR quartile (for NLR range of 3-5, HR = 2.17; for NLR range of >5-9, HR=2.46; for NLR quartile >9, HR=2.84 vs the lowest quartile [NLR<3]) (P ≤ .001). The NLR remained statistically significant in multivariable models, adjusting for age, MELD score, hepatocellular carcinoma, and ACLF severity. Additionally, NLR was a statistically significant independent predictor of length of index hospital stay and mortality within 90 days after discharge. CONCLUSION: In a retrospective analysis of patients with cirrhosis, we found NLR to associate with death within 1 year after non-elective hospitalization. In these patients, the risk of death associated with acute immune dysregulation persists long after their initial hospitalization.