Key facts and hot spots on tumor necrosis factor receptor‐associated periodic syndrome
Tumor necrosis factor receptor-associated periodic syndrome (TRAPS), formerly known as familial Hibernian fever, is the most common autosomal dominant autoinflammatory disease, resulting from mutations in the TNFRSF1A gene, encoding the 55-kD tumor necrosis factor receptor. The pathophysiologic mechanism of TRAPS remains ambiguous and only partially explained. The onset age of the syndrome is variable and the clinical scenery is characterized by recurrent episodes of high-grade fever that typically lasts 1–3 weeks, associated with migrating myalgia, pseudocellulitis, diffuse abdominal pain, appendicitis-like findings, ocular inflammatory signs, and risk of long-term amyloidosis. Fever episodes are responsive to high-dose corticosteroids, but different classes of drugs have been reported to be ineffective. The use of etanercept is unable to control systemic inflammation, while interleukin-1 blockade has been shown as effective in the control of disease activity in many patients reported so far.
KeywordsAutoinflammatory disease Interleukin-1 inhibitors Tumor necrosis factor receptor‐associated periodic syndrome
Brief summary of the hereditary autoinflammatory diseases
Fever, serositis, arthralgias or arthritides, erysipelas-like
eruption on the legs, response to colchicine prophylaxis,
amyloidosis in untreated or noncompliant patients
Colchicine, anakinra, canakinumab
p55 tumor necrosis factor receptor type-1
Fever, severe migrating muscle and joint involvement,
conjunctivitis, periorbital edema, arthralgias or arthritis,
serosal involvement, steroid responsiveness of febrile attacks,
risk of amyloidosis
Corticosteroids, etanercept, anakinra,
Fever, widespread polymorphous rash, arthralgias, abdominal
pain, diarrhea, lymph node enlargement, oral aphthosis
NSAIDs, anakinra, corticosteroids
Fever, cold-induced urticaria-like rash, conjunctivitis,
Anakinra, canakinumab, rilonacept
Fever, urticaria-like rash, conjunctivitis, arthralgias,
neurosensorial deafness, risk of amyloidosis
Fever, urticaria-like rash, uveitis, papilledema, deforming
arthritis involving large joints, neurosensorial deafness, aseptic
chronic meningopathy, risk of amyloidosis
Pauciarticular pyogenic arthritis, osteo-cartilaginous erosions of joints, cystic acne, pyogenic abscesses
Recurrent multifocal osteomyelitis, congenital dyserythropoietic anemia, chronic dermatosis resembling Sweet’s syndrome
NSAIDs, corticosteroids, anakinra, canakinumab
Intermittent fevers, granulomatous dermatitis with
ichthyosis-like changes, symmetrical granulomatous
polyarthritis, recurrent severe granulomatous panuveitis
Corticosteroids, immunosuppressive agents,
anti-TNF-α drugs, anakinra
Tumor necrosis factor receptor‐associated periodic syndrome (TRAPS, MIM #142680) is the most frequent autosomal dominant autoinflammatory disorder , caused by mutations in the TNFRSF1A gene, encoding the 55-kD type-1 receptor of TNF-α (also cited as TNFRSF1A) . Clinically speaking, TRAPS is characterized by recurrent long-lasting fever attacks variously accompanied by abdominal and/or chest pain, migratory rash and myalgia, periorbital edema, and joint and ocular symptoms [9, 10]. Serous membrane inflammation, usually in the form of polyserositis, can also occur [11, 12, 13, 14, 15]. TRAPS prevalence has not been well established, but its incidence among German children has been calculated as 5.6 per 107 person/year .
The genetic basis of TRAPS
TRAPS was first described in 1982 as familial Hibernian fever, reflecting the Irish/Scottish ancestry of patients in the very first reports , and was then found to be prevalent in patients of northern European ancestry [8, 17]. However, families of other ethnic groups such as Jewish, Arab, Puerto-Rican, and Asiatic suffering from TRAPS have also been reported . Genetic mutations associated with TRAPS have been detected on locus 12p13, a chromosome region including the gene TNFRSF1A [19, 20]. At present, 138 TNFRSF1A sequence variants have been associated with TRAPS [http://fmf.igh.cnrs.fr/infevers]. Gene mutations result in a subverted TNFRSF1A three-dimensional shape and are mainly located on exons 2, 3, 4, and 6. Moreover, they are mostly single-nucleotide missense mutations (about 94 %) and involve the first two N-terminal cysteine-rich domains CRD1 and CRD2, which are fundamental for the receptor’s three-dimensional structure. In addition, the C98Y and F112I mutations in the domain CRD3, the I170N mutation in close proximity to the transmembrane region of the TNF receptor (exon 6) together with three deletions and one deletion/insertion affecting the extracellular domain have also been reported . Variants involving cysteine residues are associated with a more severe disease phenotype and a higher risk to develop amyloidosis . Other mutations can affect the secondary structure of the receptor, such as those introducing or removing proline residues (P46L, L67P, S86P, R92P), or affecting residues involved in hydrogen bonds between different loops of the protein (T50M, I170N) . The R92Q and P46L variants are considered as non-structural low-penetrance mutations, while the D12E, V95M, and R104Q variants have been described in patients with mild or atypical manifestations [23, 24].
Pathogenetic studies related to TRAPS
The TNF-α and TNF receptor superfamilies play a key role in triggering inflammation, both locally and systemically . TNF-α is a type II transmembrane protein, known to mediate a variety of biological processes including apoptosis, cell proliferation, immune modulation, autoimmune diseases, and other pathological conditions [26, 27, 28, 29, 30, 31]. Although monocytes and macrophages are the main resources of TNF, mast cells, T and B lymphocytes, natural killer cells, neutrophils, endothelial cells, smooth and cardiac muscle cells, fibroblasts, and osteoclasts might be involved in its synthesis [32, 33, 34]. All known TNF functions result by the binding to one of two distinct receptors, designated TNFR1 (best known as TNFRSF1A, CD120a, p55) and TNFR2 (also known as TNFRSF1B, CD120b, p75), which promote different signaling pathways leading to the activation of transcription factors, such as NF-κB, c-Jun/activator protein 1 (AP-1), and mitogen activated protein kinases (MAPKs) . TNFR1 is a transmembrane protein consisting of an extracellular domain constituted by four tandem repeat cysteine-rich domains (CRD1–4), a transmembrane region, and an intracellular death domain (DD) . The N-terminal cysteine-rich domain CRD1, also called pre-ligand assembly domain (PLAD), mediates homotypic receptor interactions and allows ligand binding and signal transduction . The extracellular domain is characterized by the presence of intramolecular disulfide bridges, which constitute the binding site for TNF-α and also permits the self-assembly of the protein.
Furthermore, after activation, TNFRSF1A undergoes metalloprotease-mediated cleavage of its extracellular domain by the transmembrane glycoprotein ADAM17 (also called TNF-α converting enzyme or TACE), releasing soluble TNFR1 into the bloodstream, where it binds circulating free TNF-α and contributes to stop inflammation . In recent years, TRAPS understanding has rapidly expanded, also due to the discovery of a progressively increasing number of TNFRSF1A mutations with several pathogenetic hypotheses proposed to explain disease mechanism .
Initially, it was hypothesized that TRAPS patients expressed a constitutively active or hypersensitive TNFRSF1A, resulting in overactivation of NF-κB and increased production of proinflammatory cytokines. However, transfection studies have found that both mutant and wild-type TNFR1 activate NF-κB equally . Later, the “shedding hypothesis” suggested that structural mutations, including C33Y, T50M, C52F, and C88R, could lead to conformational changes of the protein, resulting in functional alteration and impaired cleavage of membrane-bound TNFR1, which in turn resulted in loss of self-controlled inflammation. However, some TRAPS patients exhibit normal TNFR1 shedding , and TNF-α blockade by means of the soluble p75 TNF receptor-Fc fusion protein etanercept is not constantly effective in reducing TRAPS symptoms [41, 42].
Molecular modeling experiments have also suggested that some TNFRSF1A mutations, in particular those causing abnormal intramolecular disulfide bonds, are linked with a defect in the sorting of TNFRSF1A, suggesting the “TNF receptor trafficking dysfunction” hypothesis . The abnormal oligomerization or misfolding of TNF receptors will result in a retention in the endoplasmic reticulum, leading to decreased binding to TNF and a reduction in TNF-induced apoptosis. As a consequence, enhanced sensitivity to innate immune stimuli and exaggerated autocrine production of inflammatory cytokines occur [43, 44]. In this regard, Balua et al.  and Kamata et al.  have demonstrated that peripheral blood leukocytes from TRAPS patients exhibit increased production of reactive oxygen species (ROS), which in turn potentiate MAPK signaling and release of inflammatory mediators. These data suggested that mutant TNFR1 expression leads to an increase in ROS production, resulting in the upregulation of proinflammatory cytokines such as IL-1β, TNF-α, and IL-6. Recently, interesting studies were carried out in order to investigate the link between endoplasmic reticulum and enhanced ROS production, following intracellular retention of mutant TNFR1 . It is known that accumulation of unfolded or misfolded proteins in the endoplasmic reticulum results in a cellular stress response, defined “unfolded protein response” (UPR), aimed at restoring normal cell function by halting protein translation and transduction . When cell functional recovery is not achieved, the UPR turns towards apoptosis . On this basis, Dickie et al. have suggested that an URP-associated protein, called spliced-X-box binding protein-1 (sXBP1), might be involved in the pathogenesis of TRAPS [47, 38]. In fact, lipopolysaccharide (LPS)-stimulated peripheral blood mononuclear cells from TRAPS patients demonstrated increased sXBP1 levels in comparison with healthy controls. Notably, sXBP1 levels were reduced (up to 40 %) after antioxidant administration, suggesting an association between oxidative stress, due to retention of mutated TNFR1 in the endoplasmic reticulum and increased LPS-induced levels of ROS through XBP1 pathway. Therefore, it is conceivable to assume that accumulation of mutant TNFR1 results in endoplasmic reticulum stress and XBP1 splicing, but not a full classical UPR .
In the last years, several evidences have suggested that microRNAs (miRNAs), small non-coding RNAs (18–25 nucleotides in length) that can regulate every aspect of cellular activity, from differentiation and proliferation to apoptosis, have a central role in many immune processes and in rheumatologic diseases [51, 52]. In this regard, Lucherini et al. have evaluated circulating miRNAs levels in TRAPS patients, correlating these results with parameters of disease activity and/or disease severity . TRAPS miRNA expression profile revealed a signature of six miRNAs specific for TRAPS, all significantly down-regulated in TRAPS patients in comparison with healthy controls. Interestingly, four miRNAs were found differently expressed between patients treated with anakinra versus untreated ones. In particular, miR-92a-3p and miR-150-3p expression was significantly decreased in untreated patients, while their expression was similar to controls in samples obtained during anakinra treatment. In addition, MiR-92b levels were inversely correlated with the number of febrile attacks per year, while miR-377-5p levels were positively correlated with serum amyloid-A (SAA), a relevant marker of disease activity in AIDs, suggesting that miRNA levels may be helpful in evaluating the response to treatment .
Finally, Rittore et al. have investigated about a further mechanism of TNFRSF1A regulation, founding that three polymorphisms in the promoter, resulting in an exon 2-spliced transcript-TNFR1-d2, may affect clinical features of TRAPS by means of a dual mechanism involving transcription and splicing .
TRAPS clinical features
TRAPS presents a significant heterogeneity of clinical features, probably due to the broad spectrum of TNFRSF1A mutations . The average age at disease onset is around 3 years; however, adult onset up to the sixth decade has been described as well [55, 56]. Usually fever attacks occur every 5–6 weeks, and their mean length is around 14 days, even if their duration may last many weeks . Patients with adult-onset TRAPS may also display a clinical picture mimicking familial Mediterranean fever, also in the duration of inflammatory attacks (only 1–3 days) . Typical TRAPS attacks often begin with muscle cramps, followed by fever associated with skin manifestations, arthritis, abdominal, and/or chest pain [59, 60, 61]. Serous membrane inflammation is commonly observed, usually in the form of polyserositis [11, 12, 13, 14, 15, 62]. Respiratory, genitourinary, and lymph node involvement can also occur [9, 10, 57]. Fever attacks recur either spontaneously or after minor triggers such as local injury, minor infection, variable stress, exercise, and hormonal changes. Cutaneous manifestations occur in 84 % of cases , mainly in the form of centrifugal migrant erythema. Edematous plaques, urticarial patches, and even erysipelas-like lesions represent other potential skin manifestations, histologically characterized by dermal perivascular lympho-monocytic infiltrate. These lesions are painful and warm to the touch and may predominate in the upper chest or lower limbs. Early signs consist of erythematous macules and papules in groups or isolated, and are characterized by a migratory pattern, classically centrifugal, expanding towards the periphery in large plaques in the course of days . Annular and serpiginous patches can also occur [7, 65]. Myalgia is typically migratory and associated with an overlying tender erythematous skin rash. Hull et al. showed that myalgia corresponded with edema in the muscle compartment and histologically with monocytic fasciitis . Arthralgia is more common than arthritis, which can usually occur as asymmetrical non-erosive oligo-monoarthritis, with predilection for large joints and mainly involving the knees, shoulders, elbows, hips, temporo-mandibular joints, and wrists. Sacroiliitis has also been reported . Periorbital edema is a pathognomonic clinical manifestation  and is often associated with ocular pain, conjunctivitis, or uveitis . Abdominal pain originating from inflammation of peritoneal serous membrane and/or abdominal wall muscles is another common TRAPS feature ; about one third of TRAPS patients experience laparotomy and appendectomy because of sterile acute peritonitis . With regard to genitourinary system, a long-lasting inflammation can result in ureteral strictures . Furthermore, scrotal pain due to tunica vaginalis testis involvement and neurological symptoms such as headache, aseptic meningitis, optic neuritis, and behavioral abnormalities represent other rarely reported features [70, 71].
Reactive amyloidosis is the most serious long-term complication of TRAPS, often leading to nephrotic syndrome or renal failure. Notably, patients carrying cysteine-involving TNFRSF1 mutations seem characterized by early disease onset and severe clinical manifestations, including reactive amyloidosis [72, 73]. On the contrary, low-penetrance mutations, such as R92Q, P46L, and T61I, are associated with a milder disease course, sometimes resembling a PFAPA-like phenotype, a later disease onset, and a lower risk of developing amyloidosis (2 versus 25 % of patients carrying high-penetrance TNFRSF1A variants) [74, 75]. Autonomic nervous system may also be involved by amyloidosis, giving rise to orthostatic hypotension and abnormal bowel habit . Patients often display chest pain caused by pericarditis, pleurisy, or intercostal muscle pain. Recurrent pericarditis is common in low-penetrance mutated patients and sometimes represent the only clinical manifestation, mimicking autoimmune disorders with pericardial disease [57, 76, 77, 78, 79]. Interestingly, a recent analysis of TRAPS phenotypes has found a higher rate of pericarditis in patients carrying low-penetrance variants, in comparison with patients carrying a structural mutation. According to the same analysis, low-penetrance mutated patients were less frequently associated with a chronic disease course in comparison with high-penetrance mutated ones . In addition, low-penetrance TNFRSF1A mutations were observed in about 6 % of unselected patients affected with idiopathic recurrent pericarditis (IRAP). For this reason, TRAPS mutations should be evaluated in patients with IRAP, specifically if they have a positive family history for pericarditis or periodic fever syndromes, poor response to colchicine, high number of recurrences, as well as the need for immunosuppressive agents [12, 13, 14, 78, 79, 80].
Main clinical manifestations of tumor necrosis factor receptor-associated periodic syndrome
Common and less common clinical features
Centrifugal migratory erythema, edematous plaques, annular and serpiginous patches, urticarioid lesions
Muscle cramps, migratory myalgia, fasciitis, arthralgias, oligo-monoarthritis, sacroiliitis
Headache, aseptic meningitis, optic neuritis, behavioral abnormalities
Periorbital edema, conjunctivitis, ocular pain, uveitis
Peritonitis-like picture, abdominal pain, vomiting
Ureteral strictures, scrotal pain
Chest pain, pleurisy
Orthostatic hypotension, bowel disturbance
Pericarditis, myocarditis, ventricular tachycardia, restrictive cardiomyopathy, risk of myocardial infarction and arterial thrombosis
Swollen and painful lymph nodes
Amyloidosis-related nephrotic syndrome
The identification of a mutation in the TNFRSF1A gene is needed for a definite diagnosis of TRAPS. In order to improve genetic diagnosis in adults suspected to have AIDs, Cantarini et al. have identified some variables strongly related to the probability of detecting mutations in the TNFRSF1A gene and also in the MEFV gene (which is responsible for familial Mediterranean fever). In addition, they developed, validated, and revised a diagnostic score for identifying patients at high risk to carry these mutations according to clinical manifestations, age of disease onset, and family history [55, 84, 85]. However, before this score can be recommended for widespread application, further evaluation by means of longitudinal studies on populations from different geographical areas is required.
Laboratory investigations in TRAPS
During inflammatory attacks, laboratory examinations show an increase of all inflammatory markers (erythro-sedimentation rate, C-reactive protein, fibrinogen, and haptoglobin), which usually drop to normal rates during symptom-free periods. Some patients may present neutrophil leukocytosis, thrombocytosis, hypo- or normochromic anemia, and a polyclonal gammopathy, due to stimulation of immunoglobulin synthesis by the numerous proinflammatory cytokines produced . Another interesting laboratory parameter is the detection of low serum level of the soluble TNF receptor (<1 ng/ml) during the quiescent phase of the disease, resulting from a defective release of the receptor itself by cell membranes . SAA is the acute-phase protein synthesized in the liver under stimulation by proinflammatory cytokines, which is significantly increased during inflammatory flares : its amino-terminal fragment may deposit in various organs in the form of amyloid fibrils and lead to
the development of AA-amyloidosis. Measurement of circulating SAA levels is useful for monitoring disease activity and response to therapy, disclosing minimal subclinical inflammation even in the absence of symptoms. Therefore, the occurrence of proteinuria (>0.5 g/day) and increased SAA levels (>10 mg/l) should be taken into account to early suspect and detect amyloidosis .
The calcium-binding protein S100A12 (calgranulin C) has been proposed to be involved in specific calcium-dependent signal transduction pathways, and its regulatory effect on cytoskeletal components may modulate various neutrophil activities, leading to enhanced inflammatory responses . This protein is closely correlated with disease activity and therapeutic efficacy in several diseases, showing to be a promising marker also in AIDs and TRAPS . In recent years, adipose tissue-derived peptides, such as leptin, resistin, visfatin, and adiponectin, have also drawn interest as key players in systemic inflammation. Notably, serum leptin levels significantly correlate with TRAPS severity, while serum adiponectin levels are significantly increased in TRAPS patients with reactive amyloidosis . Finally, as recently shown by Lucherini et al., serum miRNA levels will probably represent future markers of disease activity and response to therapies in TRAPS .
TRAPS management is more challenging than in other monogenic AIDs because of the genetic heterogeneity giving rise to protean multiple clinical features. Treatment depends on disease activity and its main targets are to control symptoms, guarantee a good quality of life, and prevent long-term complications (such as amyloidosis) . Few patients obtain symptomatic relief from non-steroidal antinflammatory drugs (NSAIDs), while colchicine and several immunomodulators such as methotrexate, cyclosporine, and thalidomide have very little efficacy . Corticosteroids are useful during inflammatory attacks, but patients often require escalating doses, developing metasteroidal comorbidities over time. Furthermore, corticosteroids do not prevent amyloidosis, and relapses are frequent after withdrawal. Nevertheless, corticosteroids and NSAIDs “on demand” may be considered in patients with a mild disease. Notably, data from the Eurofever project indicated that patients carrying the low-penetrance R92Q mutation seemed to respond better to NSAIDs and colchicine versus patients with other TNFRSF1A mutations . Basing on TRAPS pathogenesis, etanercept has been regarded as the primary therapeutic choice: it has shown to be effective in a subset of TRAPS patients to prevent disease flares and allow corticosteroid dose reduction [93, 94]. However, according to Bulua et al., etanercept does not completely normalize symptoms or acute-phase reactants . In addition, conflicting data have been published on the efficacy of etanercept in the treatment of TRAPS-related reactive amyloidosis, with anecdotal reports describing etanercept efficacy  and others stating that it is unable to induce amyloidosis regression . Moreover, etanercept also showed a lack or a gradually loss of efficacy over time, requiring a switch to other therapies [95, 98, 99]. Significantly, the administration of other anti-TNF agents, such as infliximab, the mouse-human chimeric monoclonal IgG1 antibody to TNF, and adalimumab, the fully humanized anti-TNF monoclonal antibody, may trigger paradoxical inflammatory attacks in TRAPS patients. Hypothetical mechanisms underlying such reactions have been suggested: (a) anti-TNF-α agents could cause apoptosis failure in peripheral blood mononuclear cells; (b) a reduced shedding infliximab-bound TNF/TNFRI from the cell surface triggers the anti-apoptotic NF-κB c-Rel subunit activation, inducing a proinflammatory response; (c) a more stable complex with the soluble TNF-α and higher avidity for the transmembrane TNF than etanercept should generate a febrile flare [100, 101, 102].
Anti-IL-1 agents are proving to be reasonable treatment options in order to prevent TRAPS relapses both in the short- and long term [92, 103]. In this regard, the recombinant IL-1 receptor antagonist anakinra has showed favorable and sustained responses, bringing about a prompt resolution of all TRAPS clinical manifestations, even the ones related to systemic amyloidosis [98, 104, 105]. However, refractoriness to anakinra in a patient carrying the T50M TNFRSF1A mutation has also been reported . Recently, two reports have showed the successful treatment with the human IgG1 anti-IL-1β monoclonal antibody canakinumab [107, 108]. In line with these findings, preliminary data from a recent phase II trial carried out on 20 TRAPS patients show that canakinumab produced a remarkable clinical benefit, which was prolonged by continued administration. Disease relapses occurring at a median of 3 months after canakinumab withdrawal were usually mild or moderate, but resolved when canakinumab was resumed . However, a partial loss of efficacy in a TRAPS patient who received canakinumab has recently been described: surprisingly, when alendronate was added to canakinumab, in order to treat a concomitant corticosteroid-induced osteoporosis, disease activity was promptly and fully controlled . These same findings were also strikingly described in a boy with mevalonate kinase deficiency syndrome, a metabolic disorder included in the family of AIDs .
Recently, since IL-6 levels may be elevated in TRAPS patients , tocilizumab, the humanized monoclonal antibody that binds specifically to both soluble and membrane-bound IL-6, has been used in etanercept- and anakinra-resistant TRAPS patients, achieving satisfactory results. A 52-year-old man carrying the C33Y TNFRSF1A mutation, in whom etanercept and anakinra had failed, was treated with tocilizumab for 6 months. During treatment, no attacks occurred and acute-phase reactants promptly dropped to normal values, suggesting that tocilizumab might be an alternative therapeutic option for TRAPS . However longer term follow-up studies are needed to ensure tocilizumab effectiveness over time.
Upregulation of proinflammatory cytokines such as IL-1β results central to the pathogenesis of many other disorders, and close connections have also been established between inflammatory and metabolic pathways. For instance, oligomers of islet amyloid polypeptides sustain persistent IL-1β positive feedback in patients with type 2 diabetes, and many disorders of bone development and remodeling might involve a still unraveled interplay among Wnt proteins, Wnt signaling antagonists, and IL-1β. Considerable progress is expected in our understanding of the molecular links between autoinflammation and human pathology, and the extraordinary advance in the field of genetics will presumably lead to a better understanding of the intimate pathogenetic mechanisms behind TRAPS, probably helping the identification of new specific therapeutic targets which might relieve our patients’ suffering in a near future.
Conflict of interest
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