Serum ANCA and Overall Mortality: A 10-Year Retrospective Cohort Study on 1,024 Italian Subjects.

Background: Antineutrophil cytoplasmic antibodies (ANCA) are primarily involved in the pathogenesis of ANCA-associated vasculitides (AAV). However, ANCA may also be present in healthy subjects and in patients with autoimmune disorders different from AAV. We hypothesized that serum ANCA are associated with a worse prognosis in disorders other than AAV. Objective: We investigated the association between the overall survival and the presence of serum ANCA in 1,024 Italian subjects with various testing indications in a 10-year interval. Methods: In this retrospective cohort study, a population of 6,285 patients (many of whom were subsequently excluded due to our criteria) who tested for ANCA at a single center in 10 years was considered, and life status and comorbidities of subjects were collected. We compared the overall survival of ANCA-positive and ANCA-negative patients by means of Kaplan-Meier curves, while a multivariable adjusted Cox regression was used to evaluate the association between the ANCA status and the outcome (death) in terms of hazard ratios (HR) with 95% confidence intervals (CI). Results: The positivity of perinuclear ANCA (pANCA) increased significantly mortality (HR, 1.60; 95% CI, 1.10-2.32), while cytoplasmic ANCA (cANCA) positivity failed to show a significant association (HR, 1.43; 95% CI, 0.77-2.68). The increased mortality rate was observed for both pANCA and cANCA in patients suffering from rheumatic disorders. No association was found between mortality and anti-MPO (HR, 0.63; 95% CI, 0.20-2.00) or anti-PR3 (HR, 0.98; 95% CI, 0.24-3.96) after adjusting for confounders. Conclusions: Serum pANCA and cANCA are independent negative prognostic factors in patients with concurrent autoimmune diseases.

Autoimmune Hepatitis During Ledipasvir/Sofosbuvir Treatment of Hepatitis C: A Case Report.

We report the case of a woman with chronic hepatitis C and idiopathic thrombocytopenic purpura (ITP) who developed autoimmune hepatitis (AIH) during antiviral therapy with ledipasvir (LDV)/sofosbuvir (SOF). The onset of acute hepatitis rose two weeks after starting treatment with LDV/SOF when HCV-RNA tested negative, suggesting a link between rapid HCV clearance and de novo autoimmune diseases. Conclusion: This case report proposes new immunologic scenarios in patients with hepatitis C virus (HCV) with laboratory or clinical signs of autoimmunity during direct-acting antiviral (DAA) therapy.

Cytoplasmic rods and rings autoantibodies developed during pegylated interferon and ribavirin therapy in patients with chronic hepatitis C.

BACKGROUND: Serum autoantibodies are frequently detected in patients with chronic HCV infection, reflecting the wide spectrum of immune reactions related to this virus. In the present study, a novel autoantibody to cytoplasmic rods and rings (RR) in chronic HCV patients was characterized. METHODS: Sera from 75 previously untreated HCV patients were investigated by indirect immunofluorescence using HEp-2 cell substrate before and during pegylated interferon (PEG-IFN)/ribavirin (RBV) therapy. HEp-2 cells were cultured and fixed either following standard protocols or with the addition of RBV in culture medium. RESULTS: In 15 out of 75 (20%) patients, analysis revealed the presence of antibodies to rod-like cytoplasmic structures ranging approximately 3-10 µm in length and rings approximately 2-5 µm in diameter. These RR structures became detectable in >95% of cells after addition of RBV in culture medium, whereas they were absent in untreated cells. Anti-RR antibodies were found in sera collected during PEG-IFN/RBV treatment only, but never detected before antiviral therapy nor in control groups. More importantly, these anti-RR antibodies were more often detected in non-responder/relapsers than in responder patients (33% versus 11%; P-value =0.037). CONCLUSIONS: An RBV-induced autoantibody was identified to a new cytoplasmic autoantigenic structure developed in HCV patients after PEG-IFN/RBV and this same structure can be induced by RBV in in vitro culture. Owing to the onset of anti-RR antibodies in PEG-IFN/RBV-treated patients and their association with a treatment failure, studies are deemed necessary to clarify whether anti-RR plays a role in the response to PEG-IFN/RBV therapy.

Overcoming a "probable" diagnosis in antimitochondrial antibody negative primary biliary cirrhosis: study of 100 sera and review of the literature.

Serum anti-mitochondrial antibodies (AMA) are the serological hallmark of primary biliary cirrhosis (PBC), yet up to 15% of PBC sera are AMA negative at routine indirect immunofluorescence (IIF) while being referred to as "probable" cases. The diagnostic role of PBC-specific antinuclear antibodies (ANA) remains to be determined. We will report herein data on the accuracy of new laboratory tools for AMA and PBC-specific ANA in a large series of PBC sera that were AMA-negative at IIF. We will also provide a discussion of the history and current status of AMA detection methods. We included IIF AMA-negative PBC sera (n=100) and sera from patients with other chronic liver diseases (n=104) that had been independently tested for IIF AMA and ANA; sera were blindly tested with an ELISA PBC screening test including two ANA (gp210, sp100) and a triple (pMIT3) AMA recombinant antigens. Among IIF AMA-negative sera, 43/100 (43%) manifested reactivity using the PBC screening test. The same test was positive for 6/104 (5.8%) control sera. IIF AMA-negative/PBC screen-positive sera reacted against pMIT3 (11/43), gp210 (8/43), Sp100 (17/43), both pMIT3 and gp210 (1/43), or both pMIT3 and Sp100 (6/43). Concordance rates between the ANA pattern on HEp-2 cells and specific Sp100 and gp210 ELISA results in AMA-negative subjects were 92% for nuclear dots and Sp100 and 99% for nuclear rim and gp210. Our data confirm the hypothesis that a substantial part of IIF AMA-negative (formerly coined "probable") PBC cases manifest disease-specific autoantibodies when tested using newly available tools and thus overcome the previously suggested diagnostic classification. As suggested by the recent literature, we are convinced that the proportion of AMA-negative PBC cases will be significantly minimized by the use of new laboratory methods and recombinant antigens.

Changes in viremia and circulating interferon-alpha during hemodialysis in hepatitis C virus-positive patients: only coincidental phenomena?

BACKGROUND: It has been hypothesized that hemodialysis (HD) treatment per se can preserve patients from an aggressive course of hepatitis C virus (HCV) infection by reduction of viral load. The aim of the present study in HCV-positive (HCV+) HD patients is to determine whether HD induces the production of interferon-alpha (IFN-alpha) and if such production can contribute to viremia reduction. METHODS: To address this issue, HCV RNA and IFN-alpha levels were determined in 11 HCV+ patients immediately before and at the end of a 4-hour dialysis session using cellulosic membranes and 24 and 48 hours later, ie, immediately before the subsequent dialysis session using the same membrane and at the end of the dialysis session. The same protocol was repeated 1 week later using a high-biocompatibility synthetic membrane. RESULTS: HCV titer decreased in all patients after dialysis (range, 3% to 95%; P = 0.001) and thereafter progressively increased and returned to basal levels within 48 hours, with a new reduction during the next dialysis treatment. There was no significant difference in the magnitude of changes in HCV titers in tests performed using cellulosic or synthetic membranes. Plasma IFN-alpha levels increased markedly after dialysis using both cellulosic (in 9 of 11 cases) and synthetic membranes (in 10 of 11 cases; P < 0.01) and returned to basal levels within 48 hours; thereafter, IFN-alpha levels increased again during the next dialysis session. In some patients, plasma IFN-alpha levels after HD were approximately 50% of the level observed after therapeutic administration of 6 million units of IFN-alpha to 4 HD patients with chronic hepatitis. CONCLUSION: Although without a proven direct cause-effect relationship between HCV level reduction and induction of IFN-alpha after dialysis, our observation suggests an additional new mechanism for the unusually mild course of HCV infection in HD patients.