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

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.

Lipoprotein cholesterol fractions are related to markers of inflammation in children and adolescents with juvenile idiopathic arthritis: a cross sectional study

“…MRP 8 (the same as S100A8) and 14 (S100A9) are calcium-binding, potent pro-inflammatory proteins produced locally by activated phagocytic myeloid cells. MRP8/14 is released as a stable heterodimer into the circulation, where it acts as a pro-inflammatory mediator, promoting activation of inflammatory cells through binding to Toll-like receptors resulting in the production of cytokines such as interleukin-1β and IL-6 that, unimpeded, amplify and perpetuate the inflammation [35, 36]. The MRP8/14 dimer is measurable in the synovial fluid and the blood, and is correlated with measures of disease activity and risk of relapse after stopping anti-inflammatory medication in JIA [37–40].…”

S100A8/A9, a potent serum and molecular imaging biomarker for synovial inflammation and joint destruction in seronegative experimental arthritis

“…In addition, IL-1Ra –/– mice also display extra-articular inflammation, such as psoriasis [34] and aortitis [31, 35]. Another important communality between certain subsets of human seronegative arthritides and IL-1Ra –/– mice is the involvement of increased IL-1 signaling, which is most apparent in sJIA patients [36, 37]. Beside increased IL-1 signaling, these patients also exhibit extraordinarily high levels of serum S100A8/A9 (a 44-times increase compared to healthy controls) suggesting a close relation between S100A8/A9 and IL-1β in inflammatory diseases.…”

“…The search for more reliable biomarkers for seronegative arthritis has resulted in several serum proteins that are associated with disease activity in patients with seronegative arthritis: IL-6, IL-17, IL-23, VEGF, and MMP3 in SpA [6, 7, 40–43], and IL-6 and IL-18 in JIA [5, 36, 44], amongst others. Although these proteins correlate with certain clinical aspects of seronegative arthritis, a major problem remains the lack of specificity, and results are often inconsistent; moreover, these putative biomarkers still await validation in cohort studies.…”

Cyclin-Dependent Kinases as Coregulators of Inflammatory Gene Expression

“…The levels of inflammatory genes must be tightly controlled because their unwanted expression in the absence of PAMP or DAMP signals may cause chronic inflammatory diseases such as rheumatoid arthritis (RA). These diseases are characterized by permanently elevated levels of cytokines such as TNF and IL-1 [24]. By contrast, insufficient inducible cytokine expression can preclude the successful clearance of the infection or inflammatory cell debris.…”