Skip to main content

Advertisement

SpringerLink
Log in

What’s new in autoinflammation?

  • Review
  • Published:
Pediatric Nephrology Aims and scope Submit manuscript

Abstract

The pathogenesis of autoinflammatory diseases has shed light on the concept of inflammation in general and on our understanding of the role of the innate immune system. The autoinflammatory diseases have a large spectrum with varying features of inflammation. The most common autoinflammatory diseases are those associated with periodic fevers. The delay in diagnosis of these four common diseases (familial Mediterranean fever, cryopyrin-associated periodic fever syndrome, mevalonate kinase deficiency, and TNF receptor-associated periodic fever syndrome) results in secondary amyloidosis of the kidney. The new work towards classification criteria for these diseases is presented. Recently a group of autoinflammatory diseases that are associated with vasculitis have also been identified. These are stimulators of interferon genes (STING)-associated vasculopathy of infancy (SAVI), which is a monogenic defect associated with excessive activity in interferon alpha and deficiency of adenosine deaminase 2, which is characterized by a polyarteritis nodosa-like picture. These monogenic diseases are now in our differential diagnosis of vasculitides. Secondary amyloidosis is a complication of autoinflammatory diseases. Understanding the inflammatory mechanisms in these diseases has led to the use of targeted biologics for this complication. It is hoped that enlightening the mechanisms underlying these monogenic autoinflammatory diseases will also teach us about the pathways in common diseases.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Ozen S (2004) Renal amyloidosis in familial Mediterranean fever. Kidney Int 65:1118–1127

    Article  Google Scholar 

  2. Sag E, Bilginer Y, Ozen S (2017) Autoinflammatory diseases with periodic fevers. Curr Rheum Rep 19:41

    Article  Google Scholar 

  3. Ozen S, Bilginer Y (2014) A clinical guide to autoinflammatory diseases: familial Mediterranean fever and next-of-kin. Nat Rev Rheumatol 10:135–147

    Article  CAS  Google Scholar 

  4. Martinon F, Burns K, Tschopp J (2002) The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-beta. Mol Cell 10:417–426

    Article  CAS  Google Scholar 

  5. Liu Y, Jesus AA, Marrero B, Yang D, Ramsey SE, Sanchez GAM, Tenbrock K, Wittkowski H, Jones OY, Kuehn HS, Lee CR, DiMattia MA, Cowen EW, Gonzalez B, Palmer I, DiGiovanna JJ, Biancotto A, Kim H, Tsai WL, Trier AM, Huang Y, Stone DL, Hill S, Kim HJ, St Hilaire C, Gurprasad S, Plass N, Chapelle D, Horkayne-Szakaly I, Foell D, Barysenka A, Candotti F, Holland SM, Hughes JD, Mehmet H, Issekutz AC, Raffeld M, McElwee J, Fontana JR, Minniti CP, Moir S, Kastner DL, Gadina M, Steven AC, Wingfield PT, Brooks SR, Rosenzweig SD, Fleisher TA, Deng Z, Boehm M, Paller AS, Goldbach-Mansky R (2014) Activated STING in a vascular and pulmonary syndrome. N Engl J Med 371:507–518

    Article  CAS  Google Scholar 

  6. Zhou Q, Wang H, Schwartz DM, Stoffels M, Park YH, Zhang Y, Yang D, Demirkaya E, Takeuchi M, Tsai WL, Lyons JJ, Yu X, Ouyang C, Chen C, Chin DT, Zaal K, Chandrasekharappa SC, P Hanson E, Yu Z, Mullikin JC, Hasni SA, Wertz IE, Ombrello AK, Stone DL, Hoffmann P, Jones A, Barham BK, Leavis HL, van Royen-Kerkof A, Sibley C, Batu ED, Gül A, Siegel RM, Boehm M, Milner JD, Ozen S, Gadina M, Chae J, Laxer RM, Kastner DL, Aksentijevich I (2016) Loss-of-function mutations in TNFAIP3 leading to A20 haploinsufficiency cause an early-onset autoinflammatory disease. Nat Genet 48:67–73

    Article  CAS  Google Scholar 

  7. Kastner DL, Aksentijevich I, Goldbach-Mansky R (2010) Autoinflammatory disease reloaded: a clinical perspective. Cell 140:784–790

    Article  CAS  Google Scholar 

  8. Noris M, Mescia F, Remuzzi G (2012) STEC-HUS, atypical HUS and TTP are all diseases of complement activation. Nat Rev Nephrol 8:622–633

    Article  CAS  Google Scholar 

  9. Ozen S, Frenkel J, Ruperto N, Gattorno M, Project E (2011) The Eurofever Project: towards better care for autoinflammatory diseases. Eur J Pediatr 170:445–452

    Article  Google Scholar 

  10. Piram M, Kone-Paut I, Lachmann HJ, Frenkel J, Ozen S, Kuemmerle-Deschner J, Stojanov S, Simon A, Finetti M, Sormani MP, Martini A, Gattorno M, Ruperto N, EUROFEVER, EUROTRAPS and the Paediatric Rheumatology International Trials Organisation (PRINTO) networks (2014) Validation of the auto-inflammatory diseases activity index (AIDAI) for hereditary recurrent fever syndromes. Ann Rheum Dis 73:2168–2173

    Article  Google Scholar 

  11. Ter Haar NM, Jeyaratnam J, Lachmann HJ, Simon A, Brogan PA, Doglio M, Cattalini M, Anton J, Modesto C, Quartier P, Hoppenreijs E, Martino S, Insalaco A, Cantarini L, Lepore L, Alessio M, Calvo Penades I, Boros C, Consolini R, Rigante D, Russo R, Pachlopnik Schmid J, Lane T, Martini A, Ruperto N, Frenkel J, Gattorno M, Paediatric Rheumatology International Trials Organisation and Eurofever Project (2016) The phenotype and genotype of mevalonate kinase deficiency: a series of 114 cases from the Eurofever Registry. Arthritis Rheum 68:2795–2805

    Article  Google Scholar 

  12. Ozen S, Demirkaya E, Amaryan G, Kone-Paut I, Polat A, Woo P, Uziel Y, Modesto C, Finetti M, Quartier P, Papadopoulou-Alataki E, Al-Mayouf SM, Fabio G, Gallizzi R, Cantarini L, Frenkel J, Nielsen S, Hofer M, Insalaco A, Acikel C, Ozdogan H, Martini A, Ruperto N, Gattorno M, Paediatric Rheumatology International Trials Organisation; Eurofever Project (2014) Results from a multicentre international registry of familial Mediterranean fever: impact of environment on the expression of a monogenic disease in children. Ann Rheum Dis 73:662–667

    Article  Google Scholar 

  13. Levy R, Gerard L, Kuemmerle-Deschner J, Lachmann HJ, Kone-Paut I, Cantarini L, Woo P, Naselli A, Bader-Meunier B, Insalaco A, Al-Mayouf SM, Ozen S, Hofer M, Frenkel J, Modesto C, Nikishina I, Schwarz T, Martino S, Meini A, Quartier P, Martini A, Ruperto N, Neven B, Gattorno M, for PRINTO and Eurofever (2015) Phenotypic and genotypic characteristics of cryopyrin-associated periodic syndrome: a series of 136 patients from the Eurofever Registry. Ann Rheum Dis 74:2043–2049

    Article  CAS  Google Scholar 

  14. Lachmann HJ, Papa R, Gerhold K, Obici L, Touitou I, Cantarini L, Frenkel J, Anton J, Kone-Paut I, Cattalini M, Bader-Meunier B, Insalaco A, Hentgen V, Merino R, Modesto C, Toplak N, Berendes R, Ozen S, Cimaz R, Jansson A, Brogan PA, Hawkins PN, Ruperto N, Martini A, Woo P, Gattorno M, Paediatric Rheumatology International Trials Organisation (PRINTO), the EUROTRAPS and the Eurofever Project (2014) 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 73:2160–2167

    Article  CAS  Google Scholar 

  15. Federici S, Vanoni F, Ben-Chetrit E, Cantarini L, Frenkel J, Goldbach-Mansky R, Gul A, Hoffman H, Koné-Paut I, Kuemmerle-Deschner J, Lachmann HJ, Martini A, Obici L, Ozen S, Simon A, Hofer M, Ruperto N, Gattorno M, for Eurofever and the Pediatric Rheumatology International Trials Organization (PRINTO) (2018) For familial Mediterranean fever, mevalonate kinase deficiency, TNF receptor-associated periodic fever syndromes, and cryopyrin-associated periodic syndrome. J Rheumatol. https://doi.org/10.3899/jrheum.180056

    Article  Google Scholar 

  16. Marek-Yagel D, Berkun Y, Padeh S, Abu A, Reznik-Wolf H, Livneh A, Pras M, Pras E (2009) Clinical disease among patients heterozygous for familial Mediterranean fever. Arthritis Rheum 60:1862–1866

    Article  CAS  Google Scholar 

  17. Rowczenio DM, Iancu DS, Trojer H, Gilbertson JA, Gillmore JD, Wechalekar AD, Tekman M, Stanescu HC, Kleta R, Lane T, Hawkins PN, Lachmann HJ (2017) Autosomal dominant familial Mediterranean fever in Northern European Caucasians associated with deletion of p.M694 residue—a case series and genetic exploration. Rheumatology (Oxford) 56:209–213

    Article  CAS  Google Scholar 

  18. Kuemmerle-Deschner JB, Ozen S, Tyrrell PN, Kone-Paut I, Goldbach-Mansky R, Lachmann H, Blank N, Hoffman HM, Weissbarth-Riedel E, Hugle B, Kallinich T, Gattorno M, Gul A, Ter Haar N, Oswald M, Dedeoglu F, Cantarini L, Benseler SM (2017) Diagnostic criteria for cryopyrin-associated periodic syndrome (CAPS). Ann Rheum Dis 76:942–947

    Article  Google Scholar 

  19. De Benedetti F, Gattorno M, Anton J, Ben-Chetrit E, Frenkel J, Hoffman HM, Koné-Paut I, Lachmann HJ, Ozen S, Simon A, Zeft A, Calvo Penades I, Moutschen M, Quartier P, Kasapcopur O, Shcherbina A, Hofer M, Hashkes PJ, Van der Hilst J, Hara R, Bujan-Rivas S, Constantin T, Gul A, Livneh A, Brogan P, Cattalini M, Obici L, Lheritier K, Speziale A, Junge G (2018) Canakinumab for the treatment of autoinflammatory recurrent fever syndromes. N Engl J Med 378:1908–1919

    Article  Google Scholar 

  20. Rodero MP, Crow YJ (2016) Type I interferon-mediated monogenic autoinflammation: the type I interferonopathies, a conceptual overview. J Exp Med 213:2527–2538

    Article  CAS  Google Scholar 

  21. Kretschmer S, Lee-Kirsch MA (2017) Type I interferon-mediated autoinflammation and autoimmunity. Curr Opin Immunol 49:96–102

    Article  CAS  Google Scholar 

  22. Remmers EF, Cosan F, Kirino Y, Ombrello MJ, Abaci N, Satorius C, Le JM, Yang B, Korman BD, Cakiris A, Aglar O, Emrence Z, Azakli H, Ustek D, Tugal-Tutkun I, Akman-Demir G, Chen W, Amos CI, Dizon MB, Kose AA, Azizlerli G, Erer B, Brand OJ, Kaklamani VG, Kaklamanis P, Ben-Chetrit E, Stanford M, Fortune F, Ghabra M, Ollier WE, Cho YH, Bang D, O'Shea J, Wallace GR, Gadina M, Kastner DL, Gül A (2010) Genome-wide association study identifies variants in the MHC class I, IL10, and IL23R-IL12RB2 regions associated with Behcet’s disease. Nat Genet 42:698–702

    Article  CAS  Google Scholar 

  23. O'Neill LA (2004) How NOD-ing off leads to Crohn disease. Nat Immunol 5:776–778

    Article  CAS  Google Scholar 

  24. Dinarello CA (2001) Novel targets for interleukin 18 binding protein. Ann Rheum Dis 60(Suppl 3):iii18–iii24

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Kim H, Sanchez GA, Goldbach-Mansky R (2016) Insights from Mendelian interferonopathies: comparison of CANDLE, SAVI with AGS, monogenic lupus. J Mol Med 94:1111–1127

    Article  CAS  Google Scholar 

  26. Chia J, Eroglu FK, Ozen S, Orhan D, Montealegre-Sanchez G, de Jesus AA, Goldbach-Mansky R, Cowen EW (2016) Failure to thrive, interstitial lung disease, and progressive digital necrosis with onset in infancy. J Am Acad Dermatol 74:186–189

    Article  Google Scholar 

  27. Batu ED, Karadag O, Taskiran EZ, Kalyoncu U, Aksentijevich I, Alikasifoglu M, Özen S (2015) A case series of adenosine deaminase 2-deficient patients emphasizing treatment and genotype-phenotype correlations. J Rheumatol 42:1532–1534

    Article  CAS  Google Scholar 

  28. Zhou Q, Yang D, Ombrello AK, Zavialov AV, Toro C, Zavialov AV, Stone DL, Chae JJ, Rosenzweig SD, Bishop K, Barron KS, Kuehn HS, Hoffmann P, Negro A, Tsai WL, Cowen EW, Pei W, Milner JD, Silvin C, Heller T, Chin DT, Patronas NJ, Barber JS, Lee CC, Wood GM, Ling A, Kelly SJ, Kleiner DE, Mullikin JC, Ganson NJ, Kong HH, Hambleton S, Candotti F, Quezado MM, Calvo KR, Alao H, Barham BK, Jones A, Meschia JF, Worrall BB, Kasner SE, Rich SS, Goldbach-Mansky R, Abinun M, Chalom E, Gotte AC, Punaro M, Pascual V, Verbsky JW, Torgerson TR, Singer NG, Gershon TR, Ozen S, Karadag O, Fleisher TA, Remmers EF, Burgess SM, Moir SL, Gadina M, Sood R, Hershfield MS, Boehm M, Kastner DL, Aksentijevich I (2014) Early-onset stroke and vasculopathy associated with mutations in ADA2. N Engl J Med 370:911–920

    Article  CAS  Google Scholar 

  29. Hashem H, Egler R, Dalal J (2017) Refractory pure red cell aplasia manifesting as deficiency of adenosine deaminase 2. J Pediatr Hematol Oncol 39:e293–e296

    Article  Google Scholar 

  30. Ozen S (2017) The changing face of polyarteritis nodosa and necrotizing vasculitis. Nat Rev Rheumatol 13:381–386

    Article  Google Scholar 

  31. Ozen S, Demirkaya E, Erer B, Livneh A, Ben-Chetrit E, Giancane G, Ozdogan H, Abu I, Gattorno M, Hawkins PN, Yuce S, Kallinich T, Bilginer Y, Kastner D, Carmona L (2016) EULAR recommendations for the management of familial Mediterranean fever. Ann Rheum Dis 75:644–651

    Article  CAS  Google Scholar 

  32. Touitou I, Sarkisian T, Medlej-Hashim M, Tunca M, Livneh A, Cattan D, Yalçinkaya F, Ozen S, Majeed H, Ozdogan H, Kastner D, Booth D, Ben-Chetrit E, Pugnère D, Michelon C, Séguret F, Gershoni-Baruch R, International Study Group for Phenotype-Genotype Correlation in Familial Mediterranean Fever (2007) Country as the primary risk factor for renal amyloidosis in familial Mediterranean fever. Arthritis Rheum 56:1706–1712

    Article  Google Scholar 

  33. Ozen S, Bilginer Y, Aktay Ayaz N, Calguneri M (2011) Anti-interleukin 1 treatment for patients with familial Mediterranean fever resistant to colchicine. J Rheumatol 38:516–518

    Article  Google Scholar 

  34. Bilginer Y, Akpolat T, Ozen S (2011) Renal amyloidosis in children. Pediatr Nephrol 26:1215–1227

    Article  Google Scholar 

  35. Okuda Y, Takasugi K (2006) Successful use of a humanized anti-interleukin-6 receptor antibody, tocilizumab, to treat amyloid A amyloidosis complicating juvenile idiopathic arthritis. Arthritis Rheum 54:2997–3000

    Article  CAS  Google Scholar 

  36. Topaloglu R, Batu ED, Orhan D, Ozen S, Besbas N (2016) Anti-interleukin 1 treatment in secondary amyloidosis associated with autoinflammatory diseases. Pediatr Nephrol 31:633–640

    Article  Google Scholar 

  37. De La Torre M, Arboleya L, Pozo S, Pinto J, Velasco J (2011) Rapid and sustained response to tocilizumab, anti-interleukin-6 receptor antibody, in a patient with nephrotic syndrome secondary to systemic juvenile idiopathic arthritis-related amyloidosis. Nephrol Dial Transplant Plus 4:178–180

    Google Scholar 

  38. Chantarogh S, Vilaiyuk S, Tim-Aroon T, Worawichawong S (2017) Clinical improvement of renal amyloidosis in a patient with systemic-onset juvenile idiopathic arthritis who received tocilizumab treatment: a case report and literature review. BMC Nephrol 18:159

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pediatrics, Hacettepe University, Ankara, Turkey

    Seza Ozen

Authors
  1. Seza Ozen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Seza Ozen.

Ethics declarations

Conflict of interest

The author has no conflict of interest in regard to this manuscript.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ozen, S. What’s new in autoinflammation?. Pediatr Nephrol 34, 2449–2456 (2019). https://doi.org/10.1007/s00467-018-4155-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00467-018-4155-4

Keywords

Search

Navigation