Antibodies against glutamic acid decarboxylase in intravenous immunoglobulin preparations can affect the diagnosis of type 1 diabetes mellitus.

BACKGROUND AND OBJECTIVES: Intravenous immunoglobulins (IVIgs) contain various autoantibodies, including those against glutamic acid decarboxylase (GADAb), a valuable biomarker of type 1 diabetes mellitus. Passive transfer of GADAb from IVIgs to patients poses a risk of misdiagnosis, and information on the specific titres of GADAb and their impact on diagnostic accuracy remains limited. This study aimed to provide further insights into the origin of GADAb detected in patient serum following IVIg infusion. MATERIALS AND METHODS: GADAb titres in IVIg products from Japan and the United States were measured using enzyme-linked immunosorbent assay-based assays. For reliable quantification, GADAb titres in pooled plasma were quantified and compared with those in the IVIg products. The determined titres were used to estimate the likelihood of passively detecting acquired GADAb in individuals receiving IVIgs. RESULTS: GADAbs were prevalent in IVIg products; however, the titres varied significantly among different lots and products. Importantly, IVIg-derived GADAb was estimated to remain detectable in patient serum for up to 100 days following a dosage of 2000 mg/kg. CONCLUSION: Clinicians should consider that IVIg preparations may contain GADAb, which can lead to false-positive results in serological assays. Careful interpretation of the assay results is key to the definitive diagnosis of type 1 diabetes mellitus.

Autoantibody profiles in intravenous immunoglobulin preparations: A possible cause of mistaken autoimmunity diagnosis.

BACKGROUND: Intravenous immunoglobulins (IVIgs) derived from the pooled plasma of thousands of donors contain numerous types of IgG molecules, including autoantibodies commonly used to diagnose autoimmunity. While these autoantibodies can cause misinterpretation of serological tests for IVIg recipients, their profiles in IVIg preparations are not fully understood. STUDY DESIGN AND METHODS: Using binding-capability based immune assays, we measured 18 varieties of clinically relevant autoantibodies in domestic blood donor-derived IVIg products. In addition, we analyzed an IVIg product from a US brand to evaluate the influence of regional and racial differences. Based on the determined autoantibody titers, pharmacokinetics of passively acquired autoantibodies and their possible detection period in serum were estimated. RESULTS: Anti-thyroglobulin (Tg), anti-thyroidperoxidase (TPO), and anti-Sjögren's-syndrome-related antigen A (SS-A) antibodies were present in considerable amounts in IVIg products. Notably, these three autoantibodies can be detected in IVIg recipients' sera for up to 3 months after infusion. DISCUSSION: To the best of our knowledge, this is the first study that analyzed multiple autoantibody profiles in both pooled plasma and IVIg products and that further evaluated their potential influences on diagnosis of autoimmunity. Clinicians should keep in mind that IVIgs contain several autoantibodies and that their infusion can produce false-positive serology results. To establish an accurate diagnosis, serological tests must be carefully interpreted and clinical symptoms should be more purposefully considered if patients are receiving IVIg therapy.

Implementation of a 20-nm pore-size filter in the plasma-derived factor VIII manufacturing process.

BACKGROUND AND OBJECTIVES: Virus inactivation and removal are important prerequisites to ensure the safety of plasma derivatives. For virus inactivation and removal in our coagulation factor VIII (FVIII) product, CROSS EIGHT M, the production process consists of solvent-detergent (S/D) treatment, two chromatography steps and virus filtration with a 35-nm pore-size filter. However, the clearance of non-enveloped viruses was not as good as that of enveloped viruses because non-enveloped viruses are resistant to S/D treatment and are too small to be removed by the filter. In this study, in order to improve the viral safety of the FVIII products, we attempted to replace the 35-nm pore-size virus filter with a 20-nm filter. MATERIALS AND METHODS: The virus-filtration process was validated for the removal of enveloped and non-enveloped model viruses. Several factors that might affect the FVIII yield on filtration were investigated to obtain a higher recovery. The biochemical properties of the FVIII products produced with the 20-nm pore-size filter were compared with those produced by the 35-nm filter. RESULTS: Virus filters of 20-nm pore size effectively removed the small non-enveloped viruses when compared with the 35-nm pore-size virus filter. The permeability of FVIII through the 20-nm pore-size filter was inversely proportional to the concentration of FVIII at filtration, and directly proportional to the amount of postfiltration solution. No differences were observed in the biochemical properties of both FVIII products, such as the structure and stability of the FVIII, the contents and multimeric structure of von Willebrand factor (vWF), and FVIII activation by thrombin. CONCLUSIONS: The virus-clearance efficiency of the FVIII product, CROSS EIGHT M, was markedly increased, in particular against small non-enveloped viruses, by changing the virus filter pore size from 35 nm to 20 nm. It was possible to implement the 20-nm pore-size filter without variation of the biochemical properties or a serious loss of FVIII.