Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

How should we approach classification of autoinflammatory diseases?

Abstract

The notion of 'autoinflammatory' disease was introduced at the end of the 1990s, and, since then, this concept has rapidly evolved. As a result, multiple definitions of autoinflammatory disease, and classifications of conditions encompassed by these definitions, have been proposed; this succession highlights advances that have been made in understanding of the innate immune system, and especially the roles of IL-1β and the inflammasome in autoinflammtory conditions. However, the definitions and classifications that have been suggested to date face a number of structure and content issues. We therefore propose another, more clinically-oriented, definition: autoinflammatory diseases are diseases with clinical signs of inflammation, associated with elevated levels of acute-phase reactants, which are attributable to dysfunction of the innate immune system, genetically-determined or triggered by an endogenous factor. From this foundation, we propose a clinically-based classification of autoinflammatory diseases, and go on to discuss how immunological diseases as a whole, including autoimmune diseases, can be appropriately located within a continuum only if the classification process is multidimensional. For this purpose, we appeal to the philosophical concepts of family resemblance and signature.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: Incorporating dysfunction of the innate and adaptive immune systems in disease classifications.

References

  1. 1

    McDermott, M. F. et al. Germline mutations in the extracellular domains of the 55 kDa TNF receptor, TNFR1, define a family of dominantly inherited autoinflammatory syndromes. Cell 97, 133–144 (1999).

    Article  Google Scholar 

  2. 2

    French FMF Consortium. A candidate gene for familial Mediterranean fever. Nat. Genet. 17, 25–31 (1997).

  3. 3

    International FMF Consortium. Ancient missense mutations in a new member of the RoRet gene family are likely to cause familial Mediterranean fever. Cell 90, 797–807 (1997).

  4. 4

    McGonagle, D. & McDermott, M. F. A proposed classification of the immunological diseases. PLoS Med. 3, e297 (2006).

    Article  Google Scholar 

  5. 5

    Hoffman, H. M., Mueller, J. L., Broide, D. H., Wanderer, A. A. & Kolodner, R. D. Mutation of a new gene encoding a putative pyrin-like protein causes familial cold autoinflammatory syndrome and Muckle–Wells syndrome. Nat. Genet. 29, 301–305 (2001).

    CAS  Article  Google Scholar 

  6. 6

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

    CAS  Article  Google Scholar 

  7. 7

    Agostini, L. et al. NALP3 forms an IL-1β-processing inflammasome with increased activity in Muckle–Wells autoinflammatory disorder. Immunity 20, 319–325 (2004).

    CAS  Article  Google Scholar 

  8. 8

    Hawkins, P. N., Lachmann, H. J. & McDermott, M. F. Interleukin-1-receptor antagonist in the Muckle–Wells syndrome. N. Engl. J. Med. 348, 2583–2584 (2003).

    Article  Google Scholar 

  9. 9

    Dinarello, C. A. Mutations in cryopyrin: bypassing roadblocks in the caspase 1 inflammasome for interleukin-1β secretion and disease activity. Arthritis Rheum. 56, 2817–2822 (2007).

    CAS  Article  Google Scholar 

  10. 10

    de Koning, H. D., Schalkwijk, J., van der Meer, J. W. & Simon, A. Successful canakinumab treatment identifies IL-1β as a pivotal mediator in Schnitzler syndrome. J. Allergy Clin. Immunol. 128, 1352–1354 (2011).

    CAS  Article  Google Scholar 

  11. 11

    Krause, K., Feist, E., Fiene, M., Kallinich, T. & Maurer, M. Complete remission in 3 of 3 anti-IL-6-treated patients with Schnitzler syndrome. J. Allergy Clin. Immunol. 129, 848–850 (2012).

    Article  Google Scholar 

  12. 12

    Arima, K. et al. Proteasome assembly defect due to a proteasome subunit beta type 8 (PSMB8) mutation causes the autoinflammatory disorder, Nakajo–Nishimura syndrome. Proc. Natl Acad. Sci. USA 108, 14914–14919 (2011).

    CAS  Article  Google Scholar 

  13. 13

    Dinarello, C. A. Blocking interleukin-1β in acute and chronic autoinflammatory diseases. J. Intern. Med. 269, 16–28 (2011).

    CAS  Article  Google Scholar 

  14. 14

    Murphy, E. A. The Logic of Medicine. 122–126 (Johns Hopkins University Press, Baltimore, 1976).

    Google Scholar 

  15. 15

    Masters, S. L., Simon, A., Aksentijevich, I. & Kastner, D. L. Horror autoinflammaticus: the molecular pathophysiology of autoinflammatory disease. Annu. Rev. Immunol. 27, 621–668 (2009).

    CAS  Article  Google Scholar 

  16. 16

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

    CAS  Article  Google Scholar 

  17. 17

    Wittgenstein, L. Philosophical investigations (Blackwell, Oxford, 1953).

    Google Scholar 

  18. 18

    Verbsky, J. W. Monogenic causes of inflammatory disease in rheumatology. Curr. Opin. Rheumatol. 24, 506–514 (2012).

    CAS  Article  Google Scholar 

  19. 19

    Boisson, B. et al. Immunodeficiency, autoinflammation and amylopectinosis in humans with inherited HOIL-1 and LUBAC deficiency. Nat. Immunol. 13, 1178–1186 (2012).

    CAS  Article  Google Scholar 

  20. 20

    Ombrello, M. J. et al. Cold urticaria, immunodeficiency, and autoimmunity related to PLCG2 deletions. N. Engl. J. Med. 366, 330–338 (2012).

    CAS  Article  Google Scholar 

  21. 21

    Lachmann, H. J. et al. Natural history and outcome in systemic AA amyloidosis. N. Engl. J. Med. 356, 2361–2371 (2007).

    CAS  Article  Google Scholar 

  22. 22

    Foucault, M. Les Mots et les Choses 17–29 (Gallimard, Paris, 1966).

    Google Scholar 

  23. 23

    Feramisco, J. D., Sadreyev, R. I., Murray, M. L., Grishin, N. V. & Tsao, H. Phenotypic and genotypic analyses of genetic skin disease through the Online Mendelian Inheritance in Man (OMIM) database. J. Invest. Dermatol. 129, 2628–2636 (2009).

    CAS  Article  Google Scholar 

  24. 24

    Samarghitean, C., Ortutay, C. & Vihinen, M. Systematic classification of primary immunodeficiencies based on clinical, pathological, and laboratory parameters. J. Immunol. 183, 7569–7575 (2009).

    CAS  Article  Google Scholar 

Download references

Author information

Affiliations

Authors

Contributions

G. Grateau and O. Steichen researched the data for the article. G. Grateau, S. Amselem and O. Steichen contributed equally to writing the article. All authors provided a substantial contribution to discussion of the content and to review and/or editing of the manuscript before submission.

Corresponding author

Correspondence to Gilles Grateau.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Table 1

Proposed categories of autoinflammatory diseases from selected classifications (PDF 94 kb)

Supplementary Table 2

Classification of autoinflammatory diseases according to their main pathological features* (DOC 41 kb)

Supplementary Figure 1

The immune disease continuum. Schematic representation of the continuum of inflammatory diseases proposed by McGonagle and McDermott.4 (PDF 149 kb)

Supplementary Figure 2

The continuum of immune diseases along the gradient of amyloidosis prevalence. (PDF 130 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Grateau, G., Hentgen, V., Stojanovic, K. et al. How should we approach classification of autoinflammatory diseases?. Nat Rev Rheumatol 9, 624–629 (2013). https://doi.org/10.1038/nrrheum.2013.101

Download citation

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing