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Hereditary transthyretin amyloidosis is caused by pathogenic variants (ATTRv) in the TTR gene. Alongside cardiac dysfunction, the disease typically manifests with a severely progressive sensorimotor and autonomic polyneuropathy. Three different drugs, tafamidis, patisiran, and inotersen, are approved in several countries, including the European Union and the United States of America. By stabilizing the TTR protein or degrading its mRNA, all types of treatment aim at preventing amyloid deposition and stopping the otherwise fatal course. Therefore, it is of utmost importance to recognize both onset and progression of neuropathy as early as possible. To establish recommendations for diagnostic and therapeutic procedures in the follow-up of both pre-symptomatic mutation carriers and patients with manifest ATTRv amyloidosis with polyneuropathy, German and Austrian experts elaborated a harmonized position. This paper is further based on a systematic review of the literature. Potential challenges in the early recognition of disease onset and progression are the clinical heterogeneity and the subjectivity of sensory and autonomic symptoms. Progression cannot be defined by a single test or score alone but has to be evaluated considering various disease aspects and their dynamics over time. The first-line therapy should be chosen based on individual symptom constellations and contra-indications. If symptoms worsen, this should promptly implicate to consider optimizing treatment. Due to the rareness and variability of ATTRv amyloidosis, the clinical course is most importantly directive in doubtful cases. Therefore, a systematic follow-up at an experienced center is crucial to identify progression and reassure patients and carriers.

Background This study assessed the prevalence of anti‐SARS‐CoV‐2 antibodies in therapeutic immunoglobulin and their impact on serological response to COVID‐19 mRNA vaccine in patients with intravenous immunoglobulin (IVIg)‐treated chronic immune neuropathies. Methods Forty‐six samples of different brands or lots of IVIg or subcutaneous IgG (SCIg) were analyzed for anti‐SARS‐CoV‐2 IgG using ELISA and chemiluminescent microparticle immunoassay (CMIA). Blood sera from 16 patients with immune neuropathies were prospectively analyzed for anti‐SARS‐CoV‐2 IgA, IgG, and IgM before and one week after IVIg infusion subsequent to consecutive COVID‐19 mRNA vaccine doses and after 12 weeks. These were compared to 42 healthy subjects. Results Twenty‐four (52%) therapeutic immunoglobulin samples contained anti‐SARS‐CoV‐2 IgG. All patients with immune neuropathies (mean age 65 ± 16 years, 25 % female) were positive for anti‐SARS‐CoV‐2 IgG after COVID‐19 vaccination. Anti‐SARS‐CoV‐2 IgA titers significantly decreased 12‐14 weeks after vaccination (p=0.02), IgG titers remained stable (p=0.2). IVIg did not significantly reduce intra‐individual anti‐SARS‐CoV‐2 IgA/IgG serum titers in immune neuropathies (p=0.69). IVIg‐derived anti‐SARS‐CoV‐2 IgG did not alter serum anti‐SARS‐CoV‐2 IgG decrease after IVIg administration (p=0.67). Conclusions Our study indicates that IVIg does not impair the antibody response to COVID‐19 mRNA vaccine in a short‐term observation, when administered a minimum of two weeks after each vaccine dose. The infusion of current IVIg preparations that contain anti‐SARS‐CoV‐2 IgG does not significantly alter serum anti‐SARS‐CoV‐2 IgG titers.

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