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  • Review Article
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From bench to bedside and back again: translational research in autoinflammation

Nature Reviews Rheumatology volume 11, pages 573–585 (2015)Cite this article

Subjects

Key Points

  • The study of IL-1β and IL-1 receptor antagonist in monogenic autoinflammatory diseases, and of IL-6 in systemic-onset juvenile idiopathic arthritis (sJIA), led to new treatment options by forward translation

  • The inefficiency of anti-TNF therapy in TNF receptor-associated periodic syndrome and the beneficial response to IL-1β blockade in sJIA stimulated reverse translational studies of the pathophysiological role of these cytokines

  • Biomarkers such as S100 proteins, IL-18 or serum amyloid A aid differential diagnosis and enable monitoring of disease activity and prediction of disease outcome

  • Autoinflammatory components define heterogeneous patient subgroups, which can be further classified by use of functional in vitro assays to identify cellular dysfunction and contribute to the understanding of disease pathophysiology

  • The integration of molecular diagnostics and in vitro analysis of dysfunctional pathways to characterize disease subgroups enable tailoring of treatment regimens and the identification of new therapeutic targets

Abstract

Translational research approaches brought major changes to the understanding and treatment options of autoinflammatory diseases. Patients with common complex multifactorial diseases such as systemic-onset juvenile idiopathic arthritis (sJIA), and particularly those with rare monogenic autoinflammatory diseases such as cryopyrin-associated periodic syndromes (CAPS) or TNF receptor-associated periodic syndrome (TRAPS), benefited from a deeper understanding of the pathophysiological mechanisms and new treatment options emerging from preclinical studies. The study of IL-1 and IL-6 in this context led to novel therapies by forward translation. Conversely, effective treatment of sJIA and TRAPS with IL-1 blockade stimulated reverse translational efforts to study the pathophysiology of these cytokines in autoinflammatory diseases. These translational efforts led to the discovery of biomarkers such as S100 proteins, IL-18 or serum amyloid A, which are components of the inflammatory process, support diagnosis and allow for monitoring of disease activity, helping to predict patient outcomes. The ongoing characterization of autoinflammatory diseases in individual patients has led to classification into heterogeneous subgroups. Further characterization of relevant subgroups and the design of tailored treatment regimens, as well as the identification of new therapeutic targets and treatment options, are the major future challenges in the field of autoinflammatory diseases, particularly for paediatric rheumatologists.

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Figure 1: Key principles of autoinflammatory pathomechanisms.
Figure 2: Bench-to-bedside-to-bench.
Figure 3: Biomarkers in autoinflammation.
Figure 4: Potential future targets in the treatment of autoinflammatory diseases.

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Acknowledgements

D.H. acknowledges support from the Interdisciplinary Centre of Clinical Research (IZKF), Münster, Germany (Clinical Research Award CRA04). D.H. and C.K. acknowledge support from the German Ministry for Education and Science (BMBF 01GM08100, AID-Net). C.K. acknowledges support from the Innovative Medical Research (IMF) program, Münster, Germany (Research Grant KE121201).

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Authors and Affiliations

  1. Department of Paediatric Rheumatology and Immunology, University Children's Hospital Münster, Albert-Schweitzer-Campus 1, Building W30, Münster, 48149, Germany

    Dirk Holzinger & Christoph Kessel

  2. Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics and Maternal-Infant Sciences, University of Genoa, Largo Daneo 3, Genova, 16132, Italy

    Alessia Omenetti

  3. 2nd Division of Paediatrics “G. Gaslini” Scientific Institute, Largo G Gaslini 5, Genoa, 16148, Italy

    Marco Gattorno

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  1. Dirk Holzinger
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  2. Christoph Kessel
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  4. Marco Gattorno
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All authors researched the data for the article, provided substantial contributions to discussion of its content, wrote the article and undertook review and/or editing of the manuscript before submission.

Corresponding author

Correspondence to Dirk Holzinger.

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Competing interests

D.H. declares that he has received speaker's fees from Novartis. M.G. declares that he has received speaker's and consultancy fees from Novartis and SOBI. C.K. and A.O. declare no competing interests.

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Holzinger, D., Kessel, C., Omenetti, A. et al. From bench to bedside and back again: translational research in autoinflammation. Nat Rev Rheumatol 11, 573–585 (2015). https://doi.org/10.1038/nrrheum.2015.79

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