Background and Aims: Distinct autoimmune diseases can share symptoms and autoantibodies, but the molecular pathways underlying this shared etiology remain poorly understood. We assessed genetic support for IL12 signaling across 27 diseases. Approach and Results: We identified a rare variant upstream of IL12A with large risk-increasing effects on autoimmune hepatitis [AIH; per-allele odds ratio (OR)=2.98, p =3×10 −9 ], primary biliary cholangitis (PBC; OR=2.80, p =2×10 −8 ), systemic sclerosis (SSc; OR=2.64, p =2×10 −11 ), Sjogren's disease (SjD; OR=1.94, p =10 −11 ), systemic lupus erythematosus (SLE; OR=1.83, p =5×10 −10 ) and multiple sclerosis (OR=1.79, p =10 −11 ). Lifetime risk for developing at least one of these conditions increased 6-fold in homozygote carriers (OR=5.73, p =0.003). We then evaluated genetic support for all 4 IL12 signaling genes and found that: (i) a non-coding variant downstream of IL12A (linked to lower gene expression) protected against 5 of the 6 diseases; (ii) an intronic variant in IL12RB2 (linked to higher gene expression) increased risk of all 6 diseases; and (iii) heterozygote carriers of rare predicted loss-of-function or missense variants in IL12RB2 had 18% lower odds of SLE (OR=0.82, p =2×10 −5 ). IL23 signaling, which shares ligand and receptor subunits with IL12, was not associated with these conditions. In epidemiologic analyses of co-prevalence, 5 of the 6 diseases strongly co-occurred with each other: AIH, PBC, SSc, SjD and SLE. Conclusions: AIH, PBC, SSc, SjD and SLE represent a distinct subset of autoimmune diseases that share genetic associations with the IL12 pathway, as well as profound co-prevalence, suggesting they may have a shared etiology and may respond to the same targeted therapeutic intervention(s).
Background and Aims: The NUC-B study showed that a 4-month course of pegylated interferon-alpha (PEG-IFNα) enhanced the outcome and reduced hepatic flares following nucleos(t)ide analog (NUC) withdrawal in HBeAg-negative chronic hepatitis B. Here, we investigated differential T- and regulatory B-cell (B REG ) changes before and during these interventions in a substudy of 41 representative patients. Approach and Results: Antigen-specific T cells were primarily evaluated using quality-controlled IFN-γ ELISpot with 15 pools of genotype-matched HBV core/small-surface peptides, confirmed by multiparameter flow cytometry. B-cell responses were tested with multiparameter flow cytometry and intracellular IL-10 staining. Broader baseline IFN-γ-producing-HBV-specific T cells correlated with higher sustained off-treatment viral control and reduced flares. PEG-IFNα led to a transient reduction in HBV-specific T cells that persisted for over 1 month after treatment. B REG producing the immunosuppressive cytokine IL-10 expanded more than 5-fold during adjuvant PEG-IFNα. The kinetics of B REG induction correlated with flares in both arms and showed a significant inverse temporal correlation with IFN-γ-producing-HBV-specific T-cell frequencies. Conclusions: Baseline breadth and magnitude of HBV-specific T cells should be evaluated as biomarkers to select patients more likely to have favorable outcomes with NUC withdrawal ±PEG-IFNα. The expansion of B REG provides insights into homeostatic mechanisms induced by PEG-IFNα and withdrawal flares, which could constrain HBV-specific T cells while limiting inflammation.
Background & Aims: Management of portal hypertension in children including primary prophylaxis of variceal bleeding is controversial due to limited understanding of mortality risk after first variceal hemorrhage (1VH). This international multicenter study was designed to advance understanding of outcomes after pediatric 1VH. Approach & Results: Center-specific characteristics and approaches to portal hypertension were determined at 44 international sites. K-means clustered the centers based upon volume and complexity of approaches [cluster 1 high (n=5), cluster 2 low (n=21), cluster 3 intermediate (n=18]). Clinical features and outcomes after 1VH were available from 345 subjects. Factors associated with overall survival (OS) and survival with native liver (SNL) were estimated by Kaplan-Meier survival curves, log rank tests, univariable and multivariable Cox regression models. OS and SNL were high in portal vein thrombosis and noncirrhotic diseases and significantly higher than biliary atresia and cirrhotic diseases ( p <.001). Diminished SNL was observed in decompensated disease [diuretics (i.e. ascites) or hospitalization at 1VH], biliary atresia with poor bile flow, cirrhotic disease, after sclerotherapy or no endoscopic intervention. Diminished OS was noted in those with cirrhosis or requiring sclerotherapy. 6-week mortality was determined and compared among clusters using average treatment effect under the Rubin causal model. Overall 6-week mortality was 4.1%, 1.4% in nonhospitalized subjects and was significantly higher in cluster 2 versus 1 centers ( P =.010). Conclusions: Immediate mortality after 1VH in children is low compared to adults. Outcomes after 1VH are diagnosis-specific and worse in decompensated disease and after sclerotherapy. Center-specific factors may influence immediate outcomes after 1VH.
