Clinical and Genetic Characteristics, Target Therapy Results in Children with Traps Syndrome (on Clinical Surveillance Data)

The complexity of diagnosing and predicting the course of TNF-receptor-associated periodic syndrome TRAPS determines the importance of studying the dependence of clinical manifestations on the variant of genetic mutation and the presence of modifier genes. We observed 5 children with an identified diagnosis of TRAPS. It was established that the disease onset in most cases is defined as a juvenile arthritis with systemic onset. Genetic variants with the replacement of cysteine residues are associated with an early debut and an aggressive course, the c.362G> A p.R121Q mutation is associated with an erosive damage to the spine. The case of a favorable course of TRAPS in siblings with a newly detected mutation is described. The development of urgent complications of TRAPS was revealed when basic therapy with canakinumab was canceled.

1. Heberden W. Commentaries on history and care of disease. London (UK): Wells and Lilly. 1802. P. 151.

2. Janeway T.C., Mosenthal H.O. An unusual paroxysmal syndrome, probably allied to recurrent vomiting, with a study of the nitrogen metabolism. Arch Intern Med. 1908;2:214–225.

3. McDermott M.F., Aksentijevich I., Galon J., et al. Germline mutations in the extracellular domains of the 55 kDa TNF receptor, TNFR1, define a family of dominantly inherited autoinflammatory syndromes. Cell. 1999;97(1):133–144. DOI: 10.1016/s0092-8674(00)80721-7

4. Emelyanchik E.Yu., Taranushenko T.E., Kirillova E.P., Ancipherova L.N., Kiselyova N.G., Cherkashina T.V., et al. Diagnostics of the mixed connective tissue disease in a child (clinical case). Sibirskoye meditsinskoye obozreniye = Siberian Medical Revew. 2015;2(92):99–103 (In Russ.).

5. de Jesus A.A., Goldbach-Mansky R. Genetically defined autoinflammatory diseases. Oral Dis. 2016;22(7):591–604. DOI: 10.1111/odi.12448

6. Horiuchi T. Trapped in TRAPS: Difficulty of Diagnosis due to Heterogeneity Internal Medicine 54(2015):1957–1958. DOI: 10.2169/internalmedicine.54.3969

7. Gattorno M., Hofer M., Federici S., et al. Classification criteria for autoinflammatory recurrent fevers. Ann Rheum Dis. 2019 Aug;78(8):1025–1032. DOI: 10.1136/annrheumdis-2019-215048

8. Williamson L.M., Hull D., Mehta R., et al. Familial Hibernian fever. Q J Med. 1982;51:469–480.

9. Touitou I., Lesage S., McDermott M., et al. Infevers: an evolving mutation database for autoinflammatory syndromes. Hum Mutat. 2004;24(3):194–198. DOI: 10.1002/humu.20080

10. D’Osualdo A., Ferlito F., Prigione I., et al. Neutrophils from patients with TNFRSF1A mutations display resistance to tumor necrosis factor- induced apoptosis: pathogenetic and clinical implications. Arthritis Rheum. 2006;54(3):998–1008. DOI: 10.1002/art.21657

11. Gaggiano C., Rigante D., Vitale A. Hints for Genetic and Clinical Differentiation of Adult-Onset Monogenic Autoinflammatory Diseases. Mediators Inflamm. 2019;2019:3293145. DOI: 10.1155/2019/3293145

12. Gattorno M. Autoinflammatory diseases in children. Questions of modern pediatrics. 2014;13(2):55–64 (In Russ.).

13. Menon S.G., Efthimiou P. Tumor Necrosis Factor-Associated Periodic Syndrome in Adults. Rheumatol Int. 2018;38(1):3–11. DOI: 10.1007/s00296-017-3820-4

14. Moiseev S.V., Rameev V.V. Canakinumab in the treatment of periodic illness and other autoinflammatory diseases – the CLUSTER study. Klinicheskaya farmakologiya i terapiya = Clinical pharmacology and therapy. 2018;27(4):59–64 (In Russ.).

15. Greco E., Aita A., Galozzi P., et al. The novel S59P mutation in the TNFRSF1A gene identified in an adult onset TNF receptor associated periodic syndrome (TRAPS) constitutively activates NF-κB pathway. Arthritis Res Ther. 2015;17(1):93. DOI: 10.1186/s13075-015-0604-7

16. Fedorov E.S., Salugina S.O., Soboleva M.K. A familial case of TRAPS in a russian population. Sovremennaya revmatologiy = Modern rheumatology. 2015;9(1):60–65 (In Russ.). DOI: 10.14412/1996-7012-2015-1-60-65

17. Holbrook J., Lara-Reyna S., Jarosz-Griffiths H., et al. Tumour necrosis factor signalling in health and disease. F1000Res. 2019;8:F1000 Faculty Rev-111. DOI: 10.12688/f1000research.17023.1

18. Bettiol A., Lopalco G., Emmi G., et al. Unveiling the Efficacy, Safety, and Tolerability of Anti-Interleukin-1 Treatment in Monogenic and Multifactorial Autoinflammatory Diseases. Int J Mol Sci. 2019;20(8):1898. DOI: 10.3390/ijms20081898

19. Hansmann S., Lainka E., Horneff G., et al. Consensus protocols for the diagnosis and management of the hereditary autoinflammatory syndromes CAPS, TRAPS and MKD/HIDS: a German PRO-KIND initiative. Pediatr Rheumatol Online J. 2020;18(1):17. DOI: 10.1186/s12969-020-0409-3

20. Gattorno M., Obici L., Cattalini M., et al. Canakinumab Treatment for Patients With Active Recurrent or Chronic TNF Receptor-Associated Periodic Syndrome (TRAPS): An Open- Label, Phase II Study. Ann Rheum Dis. 2017;76(1):173–178. DOI: 10.1136/annrheumdis-2015-209031

21. Torre F.L., Caparello M.C., Cimaz R. Canakinumab for the treatment of TNF-receptor associated periodic syndrome. Expert Rev Clin Immunol. 2017;13(6):513–523. DOI: 10.1080/1744666X.2017.1324783

22. Salugina S.O., Fedorov E.S., Kuzmina N.N., et al. Autoinflammatory diseases in rheumatology: Russian experience. Nauchno-prakticheskaya revmatologiya = Scientific and practical rheumatology. 2016;54(3):271–280 (In Russ.). DOI: 10.14412/1995-4484-2016-271-280

23. Sleptsova T.V., Alexeeva E.I., Savostyanov K.V., et al. Treating TRAPS syndrome with a previously undescribed tnf а gene receptor mutation successfully with canakinumab. Pediatricheskaya farmakologiya = Pediatric Pharmacology. 2016;13(4):399–403 (In Russ.). DOI: 10.15690/pf.v13i4.1615

24. Obici L., Merlini G. Amyloidosis in autoinflammatory syndromes. Autoimmun Rev. 2012;12(1):14–17. DOI: 10.1016/j.autrev.2012.07.016

25. Cantarini L., Rigante D., Merlini G., et al. The expanding spectrum of low-penetrance TNFRSF1A gene variants in adults presenting with recurrent inflammatory attacks: clinical manifestations and long-term follow-up. Semin Arthritis Rheum. 2014;43(6):818–823. DOI: 10.1016/j.semarthrit.2013.12.002

26. Lachmann H.J., Papa R., Gerhold K., et al. The phenotype of TNF receptor-associated autoinflammatory syndrome (TRAPS) at presentation: a series of 158 cases from the Eurofever/ EUROTRAPS international registry. Ann Rheum Dis. 2014;73(12):2160–2167. DOI: 10.1136/annrheumdis-2013-204184

27. Benedetti F.D., Gattorno M., Anton J., et al. Canakinumab for the Treatment of Autoinflammatory Recurrent Fever Syndromes. N Engl J Med. 2018;378:1908–1919. DOI: 10.1056/NEJMoa1706314

28. Yun H., Xie F., Beyl R.N. et al. Risk of Hypersensitivity to Biologic Agents Among Medicare Patients With Rheumatoid Arthritis. Arthritis Care Res (Hoboken). 2017;69(10):1526–1534. DOI: 10.1002/acr.23141

29. Nozawa T., Nishimura K., Ohya T., et al. Severe infusion reactions to tocilizumab in young children with systemic juvenile idiopathic arthritis. Int. J. Clin. Rheumatol. 2018;13(2):125–130.

30. Loyet K.M., Deng R., Liang W.C., et al. Technology comparisons for anti-therapeutic antibody and neutralizing antibody assays in the context of an anti-TNF pharmacokinetic study. J. Immunol. Methods. 2009;345(1–2):17–28. DOI: 10.1016/j.jim.2009.03.012

31. Brandse J.F., van den Brink G.R., Wildenberg M.E., et al. Loss of Infliximab into Feces Is Associated with Lack of Response to Therapy in Patients With Severe Ulcerative Colitis. Gastroenterology. 2015;149(2):350–355. DOI: 10.1053/j.gastro.2015.04.016

32. Mori F., Saretta F., Bianchi A., et al. Hypersensitivity Reactions to Monoclonal Antibodies in Children. Medicina (Kaunas). 2020;56(5):E232.