Elsevier

Autoimmunity Reviews

Volume 12, Issue 1, November 2012, Pages 38-43
Autoimmunity Reviews

Review
Tumour necrosis factor receptor-associated periodic syndrome (TRAPS): State of the art and future perspectives

https://doi.org/10.1016/j.autrev.2012.07.020Get rights and content

Abstract

Tumor necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS) is an autosomal dominant autoinflammatory disorder characterized by periodic fever episodes, arthralgia, myalgia, abdominal pain, serositis, and skin rash. TRAPS is caused by mutations in the gene encoding the TNF Receptor Super Family 1A (TNFRSF1A) on chromosome 12p13. The identification of TNFRSF1A mutations as the genetic cause of TRAPS coincided with the wider use of biological agents in medicine and raised the possibility that blocking TNF could potentially represent the primary therapeutic goal in TRAPS, thus disclosing new treatment choices for this complex disease. Anti-TNF therapy in TRAPS has been based on etanercept, a recombinant human TNFR (p75)-Fc fusion protein comprising two receptors linked by an IgG1 Fc fragment. However a decrease in responsiveness to etanercept over time has been described, and it may be due to a non-specific action of etanercept in TRAPS; its efficacy may reflect ‘generic’ anti-inflammatory properties. Long-term adherence to etanercept is poor and a significant number of patients need to switch to anti-interleukin (IL)-1β therapy. In fact, the IL-1 receptor antagonist anakinra has recently been shown to prevent disease relapses both in the short- and in the long-term, and to induce a prompt and stable disease remission.

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

  • TRAPS is an autosomal dominant disorder caused by TNFRSF1A gene mutations (12p13)

  • TRAPS is the most variable and multifaceted autoinflammatory syndrome

  • TRAPS diagnosis relies on mutational analysis and a compatible clinical picture

  • Etanercept has been shown to be efficacious in most TRAPS cases

  • Etanercept efficacy might be non-specific; resistant patients have been described

  • Interleukin-1 inhibition has been shown to induce a stable disease remission.

References (52)

  • L. Cantarini et al.

    Innate versus acquired immune response in the pathogenesis of recurrent idiopathic pericarditis

    Autoimmun Rev

    (2010)
  • S.L. Masters et al.

    Horror autoinflammaticus: the molecular pathophysiology of autoinflammatory disease

    Annu Rev Immunol

    (2009)
  • C.A. Dinarello

    Blocking interleukin-1β in acute and chronic autoinflammatory diseases

    J Intern Med

    (2011)
  • L.M. Williamson et al.

    Familial Hibernian fever

    Q J Med

    (1982)
  • B. Nedjai et al.

    Abnormal tumor necrosis factor receptor I cell surface expression and NF-kappaB activation in tumor necrosis factor receptor-associated periodic syndrome

    Arthritis Rheum

    (2008)
  • C. Sarrauste de Menthière et al.

    INFEVERS: the Registry for FMF and hereditary inflammatory disorders mutations

    Nucleic Acids Res

    (2003)
  • F.K. Chan et al.

    A domain in TNF receptors that mediates ligand-independent receptor assembly and signaling

    Science

    (2000)
  • S.L. Rebelo et al.

    Modeling of tumor necrosis factor receptor superfamily 1A mutants associated with tumor necrosis factor receptor-associated periodic syndrome indicates misfolding consistent with abnormal function

    Arthritis Rheum

    (2006)
  • N. Ravet et al.

    Clinical significance of P46L and R92Q substitutions in the tumor necrosis factor superfamily 1A gene

    Ann Rheum Dis

    (2006)
  • D. Tchernitchko et al.

    Unexpected high frequency of P46L TNFRSF1A allele in sub-Saharan West African populations

    Eur J Hum Genet

    (2005)
  • F. Bazzoni et al.

    The tumor necrosis factor ligand and receptor families

    N Engl J Med

    (1996)
  • H. Wajant et al.

    Tumor necrosis factor signaling

    Cell Death Differ

    (2003)
  • F.C. Kimberley et al.

    Falling into TRAPS-receptor misfolding in the TNF receptor 1-associated periodic fever syndrome

    Arthritis Res Ther

    (2007)
  • F. Porteu et al.

    Shedding of tumor necrosis factor receptors by activated human neutrophilis

    J Exp Med

    (1990)
  • T. Kallinich et al.

    Two familial cases with tumor necrosis factor receptor-associated periodic syndrome caused by a non-cysteine mutation (T50M) in the TNFRSF1A gene associated with severe multiorganic amyloidosis

    J Rheumatol

    (2004)
  • S. Stojanov et al.

    Clinical and functional characterisation of a novel TNFRSF1A c.605T>A/V173D cleavage site mutation associated with tumour necrosis factor receptor-associated periodic fever syndrome (TRAPS), cardiovascular complications and excellent response to etanercept treatment

    Ann Rheum Dis

    (2008)
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    These authors contributed equally to the work.

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