The therapeutic effectiveness of PPIs associated with a lack of toxicity indicates that these drugs could represent relevant adjuvants to the anti-IL-1 drugs in patients with CAPS and other IL-1-driven diseases.
Inflammasomes have also been involved in the pathogenesis of a wide range of autoinflammatory conditions that are caused by dysregulation of the IL-1 pathway, such as cryopyrinopathies and hereditary periodic fever syndromes.
IL-1 is a cytokine that exerts a pivotal role in innate immunity and in the pathogenesis of some autoimmune diseases, such as rheumatoid arthritis, and in autoinflammatory disorders, as familial Mediterranean fever and cryopyrin-associated periodic syndromes.
Consequently, we suggest that CAPS should be included in the differential diagnosis of adult patients with unexplained, recurrent inflammatory diseases, and once confirmed, the early initiation of anti-IL-1 blockade will probably prevent the development of life-threatening complications.
Areas covered: Accounting for the pivotal role of IL-1ß in the pathogenesis of CAPS, three therapeutic options, all blocking the action of IL-1ß, are currently approved: anakinra, a recombinant IL-1 receptor antagonist, the IL-1 trap rilonacept and canakinumab, a monoclonal anti-IL-1ß antibody.
Cryopyrin-associated periodic syndrome (CAPS) is a rare, heterogeneous disease entity associated with <i>NLRP3</i> gene mutations and increased interleukin-1 (IL-1) secretion.
The pattern of secretion of IL-1β and other cytokines (IL-6 and IL-1 receptor antagonist) in patients did not display the aberrancies observed in patients with CAPS and was similar to that observed in healthy controls.
Unexpectedly, IL-1α secretion is increased 10-fold, indicating that inflammatory episodes in CAPS may not be entirely a result of IL-1β but may also involve IL-1α.
Furthermore, they suggest that IL-1 receptor blockade may work in part by preventing pyronecrotic cell death, which may be an important target in NOMID and other forms of cryopyrin-associated periodic syndromes.
The difficulties of early diagnosis due to initially mild clinical symptoms and the dramatic response to anti-IL-1 therapy after diagnosis emphasize the practical relevance of considering CAPS as a differential diagnosis in these patients.
The rapid response to IL-1 inhibition suggests that the disease of this patient is driven by IL-1 and supports the conclusion that this novel mutation is pathogenic and may be associated with a new CAPS phenotype.
The discovery that dominant gain-of-function mutations in NLRP3 cause the cryopyrin-associated periodic syndromes (CAPS) and trigger spontaneous inflammasome activation and IL-1β oversecretion led to successful treatment with IL-1-blocking agents.
This should be considered when IL-1 blockade is applied as a therapeutic strategy for diseases such as cryopyrin-associated periodic syndromes or gout.
Microarray-based gene expression profiling in patients with cryopyrin-associated periodic syndromes defines a disease-related signature and IL-1-responsive transcripts.
As anti-cytokine therapies were developed for clinical use during the last decade, anti-IL-1 therapies have emerged as a highly effective treatment for cryopyrin-associated periodic syndromes (CAPSs), including the "urticaria-like rash."
CAPS and deficiency of the IL-1 receptor antagonist (DIRA), both genetic conditions with molecular defects in the IL-1 pathway, have provided a pathogenic rationale to IL-1 blocking therapies, and the impressive clinical results confirmed the pivotal role of IL-1 in human disease.
The molecular defects in CAPS and DIRA provided a therapeutic rationale for targeting IL-1 and the impressive clinical results from IL-1 blocking therapies have undoubtedly confirmed the pivotal role of IL-1 in human disease and spurred the exploration of modifying IL-1 signaling in a number of genetically complex common human diseases.
Furthermore, double-blind, placebo-controlled clinical trials have recently confirmed the efficacy and safety of rilonacept, a fusion protein of the IL-1 receptor and IgG Fc, and canakinumab, a human anti-IL-1 monoclonal antibody, as novel long-lasting agents for treating CAPS.
Although early clinical results in rheumatoid arthritis (RA) suggested that RA is not primarily an IL-1-driven disease, the discovery that the rare genetic conditions called cryopyrin-associated periodic syndromes (CAPS) were caused by overproduction of IL-1 led to clinical development and approval for these conditions.