Vol 9, No 3 (2018)
Review paper
Published online: 2018-10-17

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Doxycycline in the treatment of systemic amyloidosis with cardiac involvement.

Justyna Łyczkowska-Piotrowska1, Aleksander Salomon-Perzyński2, Agnieszka Końska2, Krzysztof Jamroziak2
Hematologia 2018;9(3):202-207.

Abstract

The leading strategy in the management of systemic amyloidosis is currently focused on reducing the production of amyloid precursor proteins. This approach is based on the use of chemotherapy in light chain amyloidosis (AL amyloidosis) or liver transplantation, or attempts to suppress transthyretin gene expression (TTR) in patients with transthyretin amyloidosis (ATTR). Recently, however, therapies have been increasingly developed to reduce the formation of amyloid deposits from circulating precursors or to eliminate already formed amyloid deposits. This approach includes, in particular, the chronic use of doxycycline, a well-known bacteriostatic antibiotic from the tetracycline group. In preclinical studies it was shown that the anti-amyloidogenic potential of doxycycline in AL amyloidosis depends on interference in the process of amyloidogenesis and the destruction of amyloid deposits. Clinical retrospective studies indicate that doxycycline used with standard chemotherapy improves prognosis in patients with AL amyloidosis with heart involvement, which is the most unfavorable prognostic group, while maintaining a favorable safety profile of therapy. In contrast, in ATTR, doxycycline appears to stabilize the clinical course of the disease. In this paper, we review literature on the role of doxycycline therapy in the treatment of systemic amyloidosis.

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References

  1. Milani P, Merlini G, Palladini G. Novel Therapies in Light Chain Amyloidosis. Kidney Int Rep. 2018; 3(3): 530–541.
  2. Westermark P, Benson MD, Buxbaum JN, et al. Nomenclature Committee of the International Society of Amyloidosis. Amyloid: toward terminology clarification. Report from the Nomenclature Committee of the International Society of Amyloidosis. Amyloid. 2005; 12(1): 1–4.
  3. Zhang C, Huang X, Li J. Light chain amyloidosis: Where are the light chains from and how they play their pathogenic role? Blood Rev. 2017; 31(4): 261–270.
  4. Quock TP, Yan T, Chang E, et al. Epidemiology of AL amyloidosis: a real-world study using US claims data. Blood Adv. 2018; 2(10): 1046–1053.
  5. Milani P, Merlini G, Palladini G. Light Chain Amyloidosis. Mediterr J Hematol Infect Dis. 2018; 10(1): e2018022.
  6. Palladini G, Merlini G. What is new in diagnosis and management of light chain amyloidosis? Blood. 2016; 128(2): 159–168.
  7. Ton VK, Mukherjee M, Judge DP. Transthyretin cardiac amyloidosis: pathogenesis, treatments, and emerging role in heart failure with preserved ejection fraction. Clin Med Insights Cardiol. 2014; 8(Suppl 1): 39–44.
  8. Hemminki K, Li X, Försti A, et al. Incidence and survival in non-hereditary amyloidosis in Sweden. BMC Public Health. 2012; 12: 974.
  9. Rocha A, Lobato L, Lobato L, et al. Transthyretin amyloidosis and the kidney. Clin J Am Soc Nephrol. 2012; 7(8): 1337–1346.
  10. Hörnsten R, Pennlert J, Wiklund U, et al. Heart complications in familial transthyretin amyloidosis: impact of age and gender. Amyloid. 2010; 17(2): 63–68.
  11. Dispenzieri A, Buadi F, Kumar SK, et al. Treatment of Immunoglobulin Light Chain Amyloidosis: Mayo Stratification of Myeloma and Risk-Adapted Therapy (mSMART) Consensus Statement. Mayo Clin Proc. 2015; 90(8): 1054–1081.
  12. Gavriatopoulou M, Musto P, Caers Jo, et al. European myeloma network recommendations on diagnosis and management of patients with rare plasma cell dyscrasias. Leukemia. 2018; 32(9): 1883–1898.
  13. Guan J, Mishra S, Falk RH, et al. Current perspectives on cardiac amyloidosis. Am J Physiol Heart Circ Physiol. 2012; 302(3): H544–H552.
  14. Dahm CN, Cornell RF, Lenihan DJ. Advances in Treatment of Cardiac Amyloid. Curr Treat Options Cardiovasc Med. 2018; 20(5): 37.
  15. Dispenzieri A, Gertz M, Kyle R, et al. Serum Cardiac Troponins and N-Terminal Pro-Brain Natriuretic Peptide: A Staging System for Primary Systemic Amyloidosis. Journal of Clinical Oncology. 2004; 22(18): 3751–3757.
  16. Wechalekar AD, Schonland SO, Kastritis E, et al. A European collaborative study of treatment outcomes in 346 patients with cardiac stage III AL amyloidosis. Blood. 2013; 121(17): 3420–3427.
  17. Dubrey SW, Cha K, Anderson J, et al. The clinical features of immunoglobulin light-chain (AL) amyloidosis with heart involvement. QJM. 1998; 91(2): 141–157.
  18. Rapezzi C, Merlini G, Quarta CC, et al. Systemic cardiac amyloidoses: disease profiles and clinical courses of the 3 main types. Circulation. 2009; 120(13): 1203–1212.
  19. Ng B, Connors LH, Davidoff R, et al. Senile systemic amyloidosis presenting with heart failure: a comparison with light chain-associated amyloidosis. Arch Intern Med. 2005; 165(12): 1425–1429.
  20. Falk RH, Alexander KM, Liao R, et al. AL (Light-Chain) Cardiac Amyloidosis: A Review of Diagnosis and Therapy. J Am Coll Cardiol. 2016; 68(12): 1323–1341.
  21. Mishra S, Guan J, Plovie E, et al. Human amyloidogenic light chain proteins result in cardiac dysfunction, cell death, and early mortality in zebrafish. Am J Physiol Heart Circ Physiol. 2013; 305(1): H95–H103.
  22. Lavatelli F, Imperlini E, Orrù S, et al. Novel mitochondrial protein interactors of immunoglobulin light chains causing heart amyloidosis. FASEB J. 2015; 29(11): 4614–4628.
  23. Oberti L, Rognoni P, Barbiroli A, et al. Concurrent structural and biophysical traits link with immunoglobulin light chains amyloid propensity. Sci Rep. 2017; 7(1): 16809.
  24. Havens MA, Hastings ML. Splice-switching antisense oligonucleotides as therapeutic drugs. Nucleic Acids Res. 2016; 44(14): 6549–6563.
  25. Maurer MS, Schwartz JH, Gundapaneni B, et al. ATTR-ACT Study Investigators. Tafamidis Treatment for Patients with Transthyretin Amyloid Cardiomyopathy. N Engl J Med. 2018; 379(11): 1007–1016.
  26. Edwards CV, Gould J, Langer AL, et al. Final analysis of the phase 1a/b study of chimeric fibril-reactive mono-clonaL ANTIBODY 11-1F4 in patients with relapsed or refractory AL amyloidosis. Am Soc Hematol. 2017; 130(Suppl 1): 509.
  27. Wechalekar AD, Whelan C. Encouraging impact of doxycycline on early mortality in cardiac light chain (AL) amyloidosis. Blood Cancer J. 2017; 7(3): e546.
  28. Salomon-Perzyński A, Końska A, Puła B. Jak leczyć pacjenta z nowo rozpoznaną amyloidozą łańcuchów lekkich pośredniego ryzyka? Rola doksycykliny w terapii amyloidozy z zajęciem serca. Hematologia. 2018; 9(3): XX–XX, doi: 10. Hem. 2018; 9(3): 26.
  29. Obici L, Cortese A, Lozza A, et al. Doxycycline plus tauroursodeoxycholic acid for transthyretin amyloidosis: a phase II study. Amyloid. 2012; 19(Suppl 1): 34–36.
  30. Ward JE, Ren R, Toraldo G, et al. Doxycycline reduces fibril formation in a transgenic mouse model of AL amyloidosis. Blood. 2011; 118(25): 6610–6617.
  31. Hata H, Sugimoto T, Ueda M, et al. Amyloid Fibril Formation of Immunoglobulin Light Chain Peptide from IHC-Negative AL Amyloidosis and Its Inhibition By Doxycycline and Epigallocatechin. Blood. 2017; 130(Suppl 1): 5331.
  32. Diomede L, Rognoni P, Lavatelli F, et al. A Caenorhabditis elegans-based assay recognizes immunoglobulin light chains causing heart amyloidosis. Blood. 2014; 123(23): 3543–3552.
  33. Cardoso I, Saraiva MJ. Doxycycline disrupts transthyretin amyloid: evidence from studies in a FAP transgenic mice model. FASEB J. 2006; 20(2): 234–239.
  34. Cardoso I, Martins D, Ribeiro T, et al. Synergy of combined doxycycline/TUDCA treatment in lowering Transthyretin deposition and associated biomarkers: studies in FAP mouse models. J Transl Med. 2010; 8(1): 74.
  35. Giorgetti S, Raimondi S, Pagano K, et al. Effect of tetracyclines on the dynamics of formation and destructuration of beta2-microglobulin amyloid fibrils. J Biol Chem. 2011; 286(3): 2121–2131.
  36. Kumar SK, Dispenzieri A, Lacy MQ, et al. Doxycycline used as post transplant antibacterial prophylaxis improves survival in patients with light chain amyloidosis undergoing autologous stem cell trans- plantation. Blood ; 120. 2012; 120(21): 3138.
  37. D'Souza A, Flynn K, Chhabra S, et al. Rationale and design of DUAL study: Doxycycline to Upgrade response in light chain (AL) amyloidosis (DUAL): A phase 2 pilot study of a two-pronged approach of prolonged doxycycline with plasma cell-directed therapy in the treatment of AL amyloidosis. Contemp Clin Trials Commun. 2017; 8: 33–38.
  38. Wixner J, Pilebro B, Lundgren HE, et al. Effect of doxycycline and ursodeoxycholic acid on transthyretin amyloidosis. Amyloid. 2017; 24(Suppl 1): 78–79.
  39. Montagna G, Cazzulani B, Obici L, et al. Benefit of doxycycline treatment on articular disability caused by dialysis related amyloidosis. Amyloid. 2013; 20(3): 173–178.
  40. Piccoli GB, Hachemi M, Molfino I, et al. Doxycycline treatment in dialysis related amyloidosis: discrepancy between antalgic effect and inflammation, studied with FDG-positron emission tomography: a case report. BMC Nephrol. 2017; 18(1): 285.



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