ReviewTumour necrosis factor receptor-associated periodic syndrome (TRAPS): State of the art and future perspectives
Introduction
Tumor necrosis factor (TNF)-α receptor‐associated periodic syndrome (TRAPS, MIM 142680) is an autosomal dominant autoinflammatory condition and is characterized by recurrent fever attacks lasting typically from 1 to 3 weeks; in addition to fever, its most common clinical manifestations include periorbital edema, conjunctivitis, a migratory erythematous plaque simulating erysipela with underlying myalgia, and arthralgia [1], [2], [3]; serosal membrane inflammation is also possible, often, but not only, in the form of polyserositis [1], [4] (Fig. 1). TRAPS is caused by mutations in the gene TNFRSF1A, located on chromosome 12p13, encoding the 55-kD receptor for TNF-α (TNFRSF1A) [5]. TRAPS belongs to the group of hereditary systemic autoinflammatory diseases (SAIDs) - formerly known as hereditary periodic fever syndromes — an expanding list of diseases characterized by unprovoked recurrent attacks of systemic inflammation with lack of autoantibodies or autoreactive T-cells [6]. In each of these syndromes a specific genetic defect which involves the regulation of innate immunity has been demonstrated, and the vast majority of these conditions is related to the activation of the interleukin-1 pathway, which results in or from a common unifying pathogenetic mechanism [7].
Section snippets
The genetic basis of TRAPS
TRAPS was initially called familial Hibernian fever, due to its first characterization in a single family of Irish/Scottish ancestry [8]. Since 1998, genome-wide searches and linkage analysis in the affected families have been used to map the susceptibility locus to chromosome 12p13 [5]. This chromosome region includes several candidate genes: CD4, LAG-3, CD27, C1R, C1S and TNFRSF1A [9]. The identification of several mutations in the TNFRSF1A gene and low levels of soluble TNFR observed in the
TRAPS pathogenesis
TNF-α is a type II transmembrane protein produced mainly by monocytes and macrophages but also by other cell types including lymphocytes, natural killer cells (NK) cells, polymorphonuclear leukocytes, keratinocytes and astrocytes. TNF is a major cytokine involved in systemic inflammation known to mediate a variety of biological processes including apoptosis, cell proliferation, immune modulation, inflammation, arthritis, autoimmune diseases and other pathological conditions [17].
TNF-α transmits
TRAPS clinical features
TRAPS is characterized by recurrent fever episodes which typically last 1 to 3 weeks on average; fever attacks recur at varying intervals, generally longer than those seen in other SAIDs, and initiate with muscle cramps or myalgia that migrates in a centrifugal pattern, followed by fever with skin, joint, abdominal and ocular manifestations [1], [2], [3]. Recurrent inflammatory episodes occur either spontaneously or after minor triggers, such as local injury, minor infection, stress, exercise
Laboratory investigations
In TRAPS, laboratory tests commonly reveal increases in indicators of inflammation during each acute inflammatory episode; in particular, marked increases are observed for erythro-sedimentation rate and C-reactive protein, as well as fibrinogen and haptoglobin, which characteristically return to normal levels during non-acute intervals. These increases can also be associated with abnormalities in blood cell count, such as neutrophil leukocytosis, thrombocytosis and hypo- or normochromic anemia,
TRAPS treatment
TRAPS treatment proves more challenging than that of other autoinflammatory syndromes due to the wide-ranging genetic heterogeneity and to the protean clinical phenotype: some patients experience significant disability over time or develop signs of renal amyloidosis, requiring novel treatment strategies with the aim of better long-term disease control. Goals of therapy for TRAPS are: i) to control symptoms, ii) to improve patients’ quality of life, iii) to prevent long-term complications.
There
Conclusions
Our understanding of the pathogenic mechanism underlying TRAPS continues to grow thanks to recent studies of mouse models. The mechanisms underlying this disease seem to be complex because the underlying biology of impaired TNFRSF1A function in TRAPS may be ligand-independent [29]. In fact, there is a growing consensus among researchers that the hyper inflammation shown in TRAPS cells is primarily independent of its TNF-α signalling function, which may be due to enhanced production of
Take-home messages
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TRAPS is an autosomal dominant disorder caused by TNFRSF1A gene mutations (12p13)
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TRAPS is the most variable and multifaceted autoinflammatory syndrome
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TRAPS diagnosis relies on mutational analysis and a compatible clinical picture
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Etanercept has been shown to be efficacious in most TRAPS cases
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Etanercept efficacy might be non-specific; resistant patients have been described
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Interleukin-1 inhibition has been shown to induce a stable disease remission.
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These authors contributed equally to the work.