Low-penetrance R92Q (p.Arg121Gln) mutation in the TNFRSF1A gene: the significance and variants of phenotypes. Successful experience with the interleukin-1 inhibitor canakinumab in a female patient, who is a carrier of R92Q mutation with a severe TRAPS phenotype

The paper is devoted to the assessment of the R92Q (p.Arg121Gln) mutation/polymorphism in the TNFRSF1A gene associated with the monogenic autoinflammatory disease – Tumor Necrosis Factor Receptor-Associated Periodic Syndrome (TRAPS). It gives data on the frequency of this gene in the general population, which is 1.3% and significantly exceeds the incidence of TRAPS. The authors describe the variants of phenotypes associated with its mutation from asymptomatic carriage to the development of a severe systemic autoinflammatory state with persistent febrile fever and a significant increase in the level of acute-phase inflammatory markers that do not respond to standard antirheumatic therapy. They present a clinical case of the high efficiency of the anti-interleukin 1β monoclonal antibody canakinumab in a female patient with a severe TRAPS phenotype, who had the R92Q mutation and hormonal dependence. Canakinumab therapy led to complete relief from all manifestations of the disease and to discontinuation of glucocorticoids. The authors conclude that the decision to prescribe therapy with biological agents should be made on the basis of the clinical severity of the disease rather than a variant of the mutation that caused it.

autoinflammatory diseases, Tumor Necrosis Factor Receptor-Associated Periodic Syndrome, low-penetrance R92Q mutation, canakinumab

1. Galon I, Aksentijevich I, McDermott F, et al. TNFRSF1A mutations and autoinflammatory syndromes. Curr Opin Immunol. 2000 Aug;12(4):479-86. doi: 10.1016/s09527915(00)00124-2.

2. Hull KM, Sholham N, Chae JJ, et al. The expanding spectrum of systemic autoinflammatory syndromes and their rheumatic manifestation. Curr Opin Rheumatol. 2003 Jan;15(1):61-9. doi: 10.1097/00002281200301000-00011.

3. Kuz'mina NN, Fedorov ES, Salugina SO, Movsisyan GR. Autoinflammatory diseases modern view on the problem. Nauchnoprakticheskaya revmatologiya = Rheumatology Science and Practice. 2009;47(1):63-75. (In Russ.). doi: 10.14412/1995-44842009-144

4. Vaster SJ, Kuis W, Grom A. Systemic JIA. New Developments in Understanding of the Pathophysiology and Therapy. Best Pract Res Clin Rheumatol. 2009 Dec;23(6):805-11. doi: 10.1016/j.berh.2009.09.003.

5. Efthimiou P, Nandini Moorthy L, Mavragani CP, et al Adult Onset Still’s Disease and Autoinflammation. Int J Inflam. 2012;2012:1-4. doi: 10.1155/2012/964751. Epub 2012 Aug 29.

6. Punzi L, Scanu A, Ramonda R, Oliviero F. Gout as autoinflammatory disease: new mechanisms for more appropriated treatment targets. Autoimmun Rev. 2012 Nov;12(1): 66-71. doi: 10.1016/j.autrev.2012.07.024. Epub 2012 Aug 2.

7. Cantarini L, Lucherini OM, Muscari I, et al. Tumor necrosis factor receptor-associated syndrome (TRAPS): State of the art and future perspectives. Autoimmun Rev. 2012 Nov;12(1):38–43. doi: 10.1016/j.autrev.2012.07.020. Epub 2012 Aug 2.

8. Gattorno M. Auto-inflammatory diseases in children. Voprosy sovremennoi pediatrii. 2014;(13):55-64. (In Russ.).

9. Lachmann HJ, Papa R, Gerhold K, et al; Paediatric Rheumatology International Trials Organisation(PRINTO); the EUROTRAPS and the Eurofever Project. 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 Dec;73(12):2160-7. doi: 10.1136/annrheumdis-2013-204184. Epub 2013 Aug 21.

10. Aganna E, Hammond L, Hawkins PN, et al. Heterogeneity among patients with tumor necrosis factor receptor-associated periodic syndrome phenotypes. Arthritis Rheum. 2003 Sep;48(9):2632-44. doi: 10.1002/art.11215.

11. Bochkov NP, Puzyrev VP, Smirnikhina SA. Klinicheskaya genetika [Clinical genetics]. Moscow: GEOTAR-Media; 2018.

12. Shinar Y, Obici L, Aksentijevich I, et al. Guidelines for the genetic diagnosis of hereditary recurrent fever. Ann Rheum Dis. 2012 Oct;71(10):1599-605. doi: 10.1136/annrheumdis-2011-201271. Epub 2012 Jun 1.

13. Aksentijevich I, Galon J, Soares M, et al. The Tumor-Necrosis-Factor Receptor Associated Periodic Syndrome: New Mutations in TNFRSF1A, Ancestral Origins, Genotype-Phenotype Studies, and Evidence for Further Genetic Heterogeneity of Periodic Fevers. Am J Hum Genet. 2001 Aug;69(2):301-14. doi: 10.1086/321976. Epub 2001 Jul 6.

14. https://infevers.umai-montpellier.fr/web/detail_mutation.php

15. Alenzi FQ. The significance and occurrence of TNF receptor polymorphisms in the Saudi population. Saudi J Biol Sci. 2016 Nov; 23(6):767-72. doi: 10.1016/j.sjbs.2016.04.015. Epub 2016 May 4.

16. Pelagatti MA, Meini A, Caorsi R, et al. Long-Term Clinical Profile of Children With the Low-Penetrance R92Q Mutation of the TNFRSF1A Gene. Arthritis Rheum. 2011 Apr;63(4):1141-50. doi: 10.1002/art.30237.

17. Toplak N, Dolezalova P, Constantin T, et al; Eastern/Central European autoinflammatory collaborating group for the Paediatric Rheumatology International Trials Organization (PRINTO) and Eurofever Project. Periodic fever syndromes in Eastern and Central European countries: results of a pediatric multinational survey. Pediatr Rheumatol Online J. 2010 Dec 2;8:29. doi: 10.1186/1546-0096-8-29.

18. Lainka E, Neudorf U, Lohse P, et al. Incidence of TNFRSF1A mutations in German children: epidemiological, clinical and genetic characteristics. Rheumatology (Oxford). 2009 Aug;48(8):987-91. doi: 10.1093/rheumatology/kep140. Epub 2009 Jun 18.

19. Alekseeva EI, Savost'yanov KV, Sleptsova TV, et al. Clinical and molecular genetic features of auto-inflammatory syndromes in children. Voprosy sovremennoi pediatrii. 2015;14(3):363-73. (In Russ.).

20. Salugina SO, Kamenets EA, Fedorov ES, et al. Results of molecular genetic screening of mutations in the NLRP3, TNFRSF1A, and MVK genes in patients with autoinflammatory diseases and systemic juvenile arthritis. Sovremennaya revmatologiya = Modern Rheumatology Journal. 2017;11(3):33-43. (In Russ.). doi: 10.14412/1996-70122017-3-33-43

21. 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 Mar;54(3):998-1008. doi: 10.1002/art.21657.

22. Ravet N, Rouaghe S, Dode C, et al. Clinical significance of P46L and R92Q substitutions in the tumor necrosis factor superfamily 1A gene. Ann Rheum Dis. 2006 Sep; 65(9):1158-62. doi: 10.1136/ard.2005.048611. Epub 2006 Mar 28.

23. Ruiz-Ortiz E, Iglesias E, Soriano A, et al. Disease Phenotype and Outcome Depending on the Age at Disease Onset in Patients Carrying the R92Q Low-Penetrance Variant in TNFRSF1A Gene. Front Immunol. 2017 Mar 27;8:299. doi: 10.3389/fimmu.2017.00299. eCollection 2017.

24. Hull KM, Drewe E, Aksentijevich I, et al. The TNF receptor-associated periodic syndrome (TRAPS): emerging concepts of an autoinflammatory disorder. Medicine (Baltimore). 2002 Sep;81(5):349-68. doi: 10.1097/00005792-200209000-00002.

25. Gattorno M, Sormani MP, D’Osualdo A, et al. A diagnostic score for molecular analysis of hereditary autoinflammatory syndromes with periodic fever in children. Arthritis Rheum. 2008 Jun;58(6):1823-32. doi: 10.1002/art.23474.

26. Federici S, Sormani MP, Ozen S, et al. Evidence-based provisional clinical classification criteria for autoinflammatory periodic fevers. Ann Rheum Dis. 2015 May;74(5): 799-805. doi: 10.1136/annrheumdis-2014206580. Epub 2015 Jan 30.

27. Fedorov ES, Salugina SO, Kuz'mina NN. Development of the doctrine of auto-inflammatory diseases in the XXI century. Nauchnoprakticheskaya revmatologiya = Rheumatology Science and Practice. 2018;56(S4):5-18. (In Russ.). doi: 10.14412/1995-44842018-5-18

28. Grandemange S, Cabasson S, Sarrabay G, et al. Clinical dose effect and functional consequences of R92Q in two families presenting with a TRAPS/PFAPA-like phenotype. Mol Genet Genomic Med. 2017 Jan 14;5(2):110-116. doi: 10.1002/mgg3.229. eCollection 2017 Mar.

29. Caorsi R, Federici S, Gattorno M. Biologic drugs in autoinflammatory syndromes. Autoimmun Rev. 2012 Nov;12(1): 81–6. doi: 10.1016/j.autrev.2012.07.027. Epub 2012 Aug 2.

30. De Benedetti F, Gattorno M, Anton J, et al Canakinumab for the Treatment of Autoinflammatory Recurrent Fever Syndromes. N Engl J Med. 2018 May 17; 378(20):1908-19. doi: 10.1056/NEJMoa1706314.