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Systemic immunoglobulin light chain amyloidosis

Abstract

Systemic immunoglobulin light chain amyloidosis is a protein misfolding disease caused by the conversion of immunoglobulin light chains from their soluble functional states into highly organized amyloid fibrillar aggregates that lead to organ dysfunction. The disease is progressive and, accordingly, early diagnosis is vital to prevent irreversible organ damage, of which cardiac damage and renal damage predominate. The development of novel sensitive biomarkers and imaging technologies for the detection and quantification of organ involvement and damage is facilitating earlier diagnosis and improved evaluation of the efficacy of new and existing therapies. Treatment is guided by risk assessment, which is based on levels of cardiac biomarkers; close monitoring of clonal and organ responses guides duration of therapy and changes in regimen. Several new classes of drugs, such as proteasome inhibitors and immunomodulatory drugs, along with high-dose chemotherapy and autologous haematopoietic stem cell transplantation, have led to rapid and deep suppression of amyloid light chain production in the majority of patients. However, effective therapies for patients with advanced cardiac involvement are an unmet need. Passive immunotherapies targeting clonal plasma cells and directly accelerating removal of amyloid deposits promise to further improve the overall outlook of this increasingly treatable disease.

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Fig. 1: Schematic pathways involved in AL amyloid fibril formation.
Fig. 2: Kinetics of fibril formation in vitro.
Fig. 3: Organ involvement in systemic AL amyloidosis.
Fig. 4: Diagnostic algorithm for systemic AL amyloidosis.
Fig. 5: Histological evidence of amyloid fibrils in tissue.
Fig. 6: Risk stratification of patients with AL amyloidosis.
Fig. 7: Risk-adapted treatment of AL amyloidosis.

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Acknowledgements

G.M. and G.P. are supported in part by grants from ‘Associazione Italiana per la Ricerca sul Cancro–Special Program Molecular Clinical Oncology 5 per mille n. 9965’, from CARIPLO ‘Structure-function relation of amyloid: understanding the molecular bases of protein misfolding diseases to design new treatments n. 2013–0964’ and from CARIPLO ‘Molecular mechanisms of immunoglobulin toxicity in age-related plasma cell dyscrasias n. 2015–0591’. G.P. is supported in part by the Bart Barlogie Young Investigator Award from the International Myeloma Society.

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Nature Reviews Disease Primers thanks J. Blade, R. Comenzo, B. Hazenberg, S. Ikeda, A. Jaccard, R. Linke and the other, anonymous referee(s) for their contribution to the peer review of this work.

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Introduction (G.M.); Epidemiology (A.D. and M.A.G.); Mechanisms/pathophysiology (G.M.); Diagnosis, screening and prevention (A.D., G.P., P.N.H. and M.A.G.); Management (G.M., A.D., V.S., S.O.S., G.P., P.N.H. and M.A.G.); Quality of life (V.S.); Outlook (G.M. and P.N.H.); Overview of the Primer (G.M.).

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Correspondence to Giampaolo Merlini.

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Competing interests

G.M. is on the advisory board for Caelum, Janssen and Pfizer and has received travel support from Janssen and Prothena. A.D. receives research support from Alnylam, Celgene, GlaxoSmithKline, Pfizer and Takeda and has received research support from Prothena. V.S. sits on the advisory boards of Caelum, Janssen, receives research support from Celgene, Janssen and Takeda and has received research support from Prothena. S.O.S. has received honoraria and research support from Prothena and receives honoraria from Janssen, travel support from Jazz and Takeda and research support from Janssen and Sanofi. G.P. sits on the advisory board of Janssen, has received honoraria from Prothena and receives honoraria from Sebia and travel support from Celgene. P.N.H. receives honoraria from Alnylam and GlaxoSmithKline and is a director and stockholder of Pentraxin Therapeutics. M.A.G. receives honoraria from Abbvie, Alnylam, Amgen, Annexon, Appellis, Celgene, Ionis, Janssen, Johnson and Johnson, Medscape, Physicians Education Resource, Prothena, Research to Practice, Spectrum and Teva and receives research support from Spectrum.

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Merlini, G., Dispenzieri, A., Sanchorawala, V. et al. Systemic immunoglobulin light chain amyloidosis. Nat Rev Dis Primers 4, 38 (2018). https://doi.org/10.1038/s41572-018-0034-3

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