Diagnostikk og behandling av autoimmun hepatitt

Autoimmun hepatitt er en kronisk leversykdom som ubehandlet kan føre til levercirrhose og leversvikt. Majoriteten av pasientene responderer godt på standard immunsuppressiv behandling, men noen opplever bivirkninger eller manglende behandlingseffekt. Diagnostikk, evaluering av behandlingsrespons og valg av annenlinjebehandling kan være utfordrende. Vi sammenfatter her oppdatert kunnskap om diagnostikk og behandling av pasienter med komplisert autoimmun hepatitt.publishedVersio

The persistence of anti-Spike antibodies following two SARS-CoV-2 vaccine doses in patients on immunosuppressive therapy compared to healthy controls—a prospective cohort study

The durability of vaccine-induced humoral immunity against SARS-CoV-2 in patients with immune mediated inflammatory diseases (IMIDs) on immunosuppressive therapy is not known. The aim of this study was to compare the persistence of anti-Spike antibodies following two-dose SARS-CoV-2 vaccination between IMID patients and healthy controls and to identify factors associated with antibody decline.publishedVersio

Gut and Liver B Cells of Common Clonal Origin in Primary Sclerosing Cholangitis-Inflammatory Bowel Disease

B cells express an antigen‐specific B‐cell receptor (BCR) and may contribute to liver inflammation by recognizing shared antigens in the gut and liver. Herein, we used high‐throughput BCR sequencing of the immunoglobulin heavy chain, specifically the complementarity‐determining region 3 (CDR3), to characterize the B‐cell repertoire of freshly‐frozen paired gut and liver tissue samples from patients with primary sclerosing cholangitis (PSC) and concurrent inflammatory bowel disease (IBD) (PSC‐IBD, n = 10) and paired formalin‐fixed paraffin‐embedded (FFPE) tumor‐adjacent normal colon and liver tissue from patients with colorectal liver metastases (controls, n = 10). We observed significantly greater numbers of B cells (P < 0.01) and unique B‐cell clonotypes (P < 0.05) in gut samples compared to liver samples of patients with PSC‐IBD, whereas BCR sequences in FFPE normal gut and liver samples were nearly absent (14 ± 5 clonotypes; mean ± SD; n = 20). In PSC‐IBD, an average of 8.3% (range, 1.6%‐18.0%) of B‐cell clonotypes were found to overlap paired gut and liver samples following the exclusion of memory clonotypes reported in the blood of healthy controls. Overlapping gut and liver clonotypes showed stronger evidence of antigen‐driven activation compared to non‐overlapping clonotypes, including shorter CDR3 lengths and higher counts of somatic hypermutation (P < 0.0001). Conclusion: A proportion of gut and liver B cells originate from a common clonal origin (i.e., likely to recognize the same antigen) in patients with PSC which suggests B‐cell antigens are shared across the gut–liver axis. (Hepatology Communications 2018; 00:000‐000

Diagnostikk og behandling av autoimmun hepatitt

Autoimmun hepatitt er en kronisk leversykdom som ubehandlet kan føre til levercirrhose og leversvikt. Majoriteten av pasientene responderer godt på standard immunsuppressiv behandling, men noen opplever bivirkninger eller manglende behandlingseffekt. Diagnostikk, evaluering av behandlingsrespons og valg av annenlinjebehandling kan være utfordrende. Vi sammenfatter her oppdatert kunnskap om diagnostikk og behandling av pasienter med komplisert autoimmun hepatitt

Effect of gender on mortality and causes of death in cirrhotic patients with gastroesophageal varices. A retrospective study in Norway

Background & aims The prognostic role of gender in patients with liver cirrhosis is not fully understood. Our primary aim was to assess how gender affects cumulative incidence and risk of death without liver transplantation (LT) in cirrhotic patients with gastroesophageal varices. Secondary aims were to assess the relationship between gender and cause specific death, risk of variceal bleeding and incidence rates of gastroesophageal varices in patients with cirrhosis. Methods All new patients with gastroesophageal varices due to liver cirrhosis at Oslo University Hospital between 2006 and May 2016 were identified. Clinical data were retrieved retrospectively from hospital files. Causes of death were classified according to a specified protocol in cases of in-hospital-death, otherwise by data from the Norwegian Death Registry. Competing risk analyses were used to calculate cumulative incidences and risks of i) all-cause death, ii) cause-specific death and iii) variceal bleeding or re-bleeding. Results Cumulative one- and five years incidence of death without LT in 266 included patients were 28% and 51%, respectively. In univariate analysis, risk of death was positively associated with age, Child Pugh class, alcoholic liver disease and presentation with variceal bleeding, and negatively associated with female sex. In a multivariate model, risk of death without LT was associated with female sex (SHR 0.59 [0.40–0.86]), age (SHR 1.05 [1.04–1.07] per year), Child Pugh class B (SHR 1.54 [1.03–2.32]) and Child Pugh class C (SHR 4.29 [2.57–7.17]). Variceal bleeding caused 27% of deaths. Adjusting for age and Child Pugh score, a trend towards reduced risk of death due to variceal bleeding was seen in women (SHR 0.53; [0.26–1.06]). High alcohol consumption was associated with increased risk of first variceal bleeding, both at univariate analysis (SHR 7.73 [1.71–34.9]) and multivariate analysis (SHR 13.9 [2.51–77.0]). Conclusions Reduced mortality due to variceal bleeding may contribute to improved survival without LT in cirrhotic women with gastroesophageal varices

Immunogenicity and safety of a three-dose SARS-CoV-2 vaccination strategy in patients with immune-mediated inflammatory diseases on immunosuppressive therapy

Objectives Humoral vaccine responses to SARS-CoV-2 vaccines are impaired and short lasting in patients with immune-mediated inflammatory diseases (IMID) following two vaccine doses. To protect these vulnerable patients against severe COVID-19 disease, a three-dose primary vaccination strategy has been implemented in many countries. The aim of this study was to evaluate humoral response and safety of primary vaccination with three doses in patients with IMID.Methods Patients with IMID on immunosuppressive therapy and healthy controls receiving three-dose and two-dose primary SARS-CoV-2 vaccination, respectively, were included in this prospective observational cohort study. Anti-Spike antibodies were assessed 2–4 weeks, and 12 weeks following each dose. The main outcome was anti-Spike antibody levels 2–4 weeks following three doses in patients with IMID and two doses in controls. Additional outcomes were the antibody decline rate and adverse events.Results 1100 patients and 303 controls were included. Following three-dose vaccination, patients achieved median (IQR) antibody levels of 5720 BAU/mL (2138–8732) compared with 4495 (1591–6639) in controls receiving two doses, p=0.27. Anti-Spike antibody levels increased with median 1932 BAU/mL (IQR 150–4978) after the third dose. The interval between the vaccine doses and vaccination with mRNA-1273 or a combination of vaccines were associated with antibody levels following the third dose. Antibody levels had a slower decline-rate following the third than the second vaccine dose, p&lt;0.001. Adverse events were reported by 464 (47%) patients and by 196 (78%) controls. Disease flares were reported by 70 (7%) patients.Conclusions This study shows that additional vaccine doses to patients with IMID contribute to strong and sustained immune-responses comparable to healthy persons vaccinated twice, and supports repeated vaccination of patients with IMID.Trial registration number NCT04798625

HLA-DQA1∗05 Genotype and Immunogenicity to Tumor Necrosis Factor-α Antagonists: A Systematic Review and Meta-analysis

Background & Aims: Identifying patients at high risk of immunogenicity is important when selecting tumor necrosis factor (TNF)-α antagonists in patients with immune-mediated inflammatory diseases (IMIDs). We evaluated the association HLA-DQA1∗05 genotype and risk of immunogenicity with TNF-α antagonists. Methods: Through a systematic review through July 14, 2022, we identified studies in patients with IMIDs treated with TNF-α antagonists, which reported the risk of immunogenicity and/or secondary loss of response in patients with HLA-DQA1∗05 variants. Primary outcome was risk of immunogenicity. We performed random effects meta-analysis and used GRADE to appraise certainty of evidence. Results: On meta-analysis of 13 studies (3756 patients; median follow-up, 12 months; 41% with variants), HLA-DQA1∗05 variants were associated with 75% higher risk of immunogenicity compared with non-carriers (relative risk, 1.75; 95% confidence interval, 1.37-2.25) with considerable heterogeneity (I2 = 62%) (low certainty evidence). Positive and negative predictive values of HLA-DQA1∗05 variants for predicting immunogenicity were 30% and 80%, respectively. Proactive therapeutic drug monitoring, but not concomitant use of IMMs, IMIDs, and TNF-α antagonist-type, modified this association. Patients with HLA-DQA1∗05 variants experienced 2.2-fold higher risk of secondary loss of response (6 cohorts; relative risk, 2.24; 95% confidence interval, 1.67-3.00; I2 = 0%) (moderate certainty evidence). Conclusion: Variants in HLA-DQA1∗05 are associated with an increased risk in immunogenicity and secondary loss of response in patients with IMIDs treated with TNF-α antagonists. However, the positive and negative predictive value is moderate, and decisions on concomitant use of IMMs to prevent immunogenicity should be individualized based on all factors that influence drug clearance