Quantification of polyreactive immunoglobulin G facilitates the diagnosis of autoimmune hepatitis.

BACKGROUND AND AIMS: Detection of autoantibodies is a mainstay of diagnosing autoimmune hepatitis (AIH). However, conventional autoantibodies for the workup of AIH lack either sensitivity or specificity, leading to substantial diagnostic uncertainty. We aimed to identify more accurate serological markers of AIH with a protein macroarray. APPROACH AND RESULTS: During the search for more-precise autoantibodies to distinguish AIH from non-AIH liver diseases (non-AIH-LD), IgG antibodies with binding capacities to many human and foreign proteins were identified with a protein macroarray and confirmed with solid-phase ELISAs in AIH patients. Subsequently, polyreactive IgG (pIgG) was exemplarily quantified by reactivity against human huntingtin-interacting protein 1-related protein in bovine serum albumin blocked ELISA (HIP1R/BSA). The diagnostic fidelity of HIP1R/BSA binding pIgG to diagnose AIH was assessed in a retrospective training, a retrospective multicenter validation, and a prospective validation cohort in cryoconserved samples from 1,568 adults from 10 centers from eight countries. Reactivity against HIP1R/BSA had a 25% and 14% higher specificity to diagnose AIH than conventional antinuclear and antismooth muscle antibodies, a significantly higher sensitivity than liver kidney microsomal antibodies and antisoluble liver antigen/liver pancreas antigen, and a 12%-20% higher accuracy than conventional autoantibodies. Importantly, HIP1R/BSA reactivity was present in up to 88% of patients with seronegative AIH and in up to 71% of AIH patients with normal IgG levels. Under therapy, pIgG returns to background levels of non-AIH-LD. CONCLUSIONS: pIgG could be used as a promising marker to improve the diagnostic workup of liver diseases with a higher specificity for AIH compared to conventional autoantibodies and a utility in autoantibody-negative AIH. Likewise, pIgG could be a major source of assay interference in untreated AIH.

Antibodies against MYC-Associated Zinc Finger Protein: An Independent Marker in Acute Coronary Syndrome?

INTRODUCTION: Atherosclerosis is considered the pathophysiology underlying cardiovascular (CVD), cerebrovascular, and peripheral vascular diseases. Evidence supporting an autoimmune component is emerging, with imaging studies correlating MYC-associated zinc finger protein antibody (MAZ-Ab) optical density (OD) with plaque activity. This study compares MAZ-Ab OD on ELISA testing among patients presenting with acute coronary syndromes (ACSs) to healthy controls and investigates the association of MAZ-Ab to traditional CVD risk factors. METHODS: Patients admitted with ACSs between August 2007 and July 2011 were included. Serum samples taken at presentation were retrospectively tested for MAZ-Ab and compared with serum from healthy volunteers with no CVD risk factors. Large-scale assessment of post-ACS prognostic relevance was performed using the established PLATO cohort. RESULTS: In total 174 ACS patients and 96 controls were included. Among ACS patients, median MAZ-Ab OD was higher compared with controls (0.46 vs. 0.27; p = 0.001). Although the majority of ACS patients (116/174; 67%) had suffered from a ST-elevation myocardial infarction, no significant differences in MAZ-Ab titers were evident between ACS subtypes (p = 0.682). No associations between MAZ-Ab OD and conventional CVD risk factors were identified. Large-scale testing revealed no prognostic stratification regarding reinfarction (OR 1.04 [95% CI: 0.94-1.16]; p = 0.436). CONCLUSION: MAZ-Ab OD was higher or all ACS phenotypes compared with controls. Given current understanding of MAZ-Ab function, these findings support an autoimmune component to CVD independent of conventional risk factors and indeed the extent of end-organ damage.

Anti-MYC-associated zinc finger protein antibodies are associated with inflammatory atherosclerotic lesions on 18F-fluorodeoxyglucose positron emission tomography.

BACKGROUND AND AIMS: Atherosclerosis is a chronic inflammatory process of vessel walls responsible for coronary, cerebrovascular and peripheral vascular disease, which together account for the majority of non-infective global deaths. Whilst great emphasis has been placed on lifestyle factors, a growing body of evidence supports an autoimmune component to atherosclerosis. This study evaluates a novel autoantibody against MYC-associated zinc finger protein (MAZ-Ab) as a potential marker of atherosclerosis. It compares MAZ-Ab to activity on whole-body positron-emission tomography/computed tomography (PET/CT) attributable to atherosclerosis. METHODS: Antibody screening using protein arrays was performed in patients with angiographically-proven ischaemic heart disease. Following MAZ-Ab detection, an ELISA for large-scale testing was developed. An a priori group of unselected patients attending for unrelated 18F-fluorodeoxyglucose (FDG) PET/CT was prospectively enrolled. Each completed a structured questionnaire under supervision and provided serum for analysis. PET/CT scans were evaluated for inflammatory arterial lesions. Whole-body arterial inflammatory burden was then correlated with ELISA optical density for MAZ-Ab. RESULTS: Protein array testing identified IgG anti-MAZ antibodies in 4/6 (67%) patients with ischemic heart disease, versus 0/10 controls. Significant positive correlations between MAZ-Ab and both increasing number of PET positive inflammatory atherosclerostic lesions (p = 0.023) and whole-body arterial inflammatory burden (p = 0.002) were shown. No traditional atherosclerotic risk factor correlated with MAZ-Ab. CONCLUSIONS: A quantitative association between MAZ-Ab optical density on ELISA and the cumulative inflammatory burden of atherosclerosis on 18F-FDG PET/CT could be shown. These findings provide further evidence for an autoimmune component in atherosclerosis and suggest MAZ-Abs as a potential biomarker for atherosclerotic disease.

Essential mixed cryoglobulinemia type III with leukocytoclastic vasculitis: remission by rituximab.

We report about a 39-year-old female patient with severe essential mixed cryoglobulinemia of type III with leukocytoclastic vasculitis. The patient was admitted into our hospital with mesenteric lymphangiitis, which caused enteral perforation, sepsis, and pneumonia. Cryoglobulins, cryocrit, Ig-titers, and biopsy were positive for mixed cryoglobulinemia type III. We detected no signs of hepatitis C, B, or any other infectious disease. At first, disease activity could be kept under control with high doses of glucocorticoids and multiple cyclophosphamide pulses. However, after therapy with three pulses of rituximab, steroids were stopped, and the patient has not presented any symptoms for 2 years. Therefore, we suggest that rituximab affected her disease rapidly and effectively. In conclusion, rituximab is an alternative therapy for mixed cryoglobulinemia of type III with leukocytoclastic vasculitis.