Tumor Necrosis Factor Receptor 1-associated Periodic Syndrome

TRAPS is characterized by recurrent inflammatory episodes, which may be preceded by malaise and headaches [1]. Symptom onset typically occurs in early childhood, but adult-onset cases have been reported repeatedly [2]. Patients suffer from bouts of fever, skin rash, arthralgia and arthritis, myalgia, and abdominal pain. Late-onset TRAPS may also be accompanied by pleuritic chest pain. With regard to dermatological findings, centrifugal migratory erythema is generally described as characteristic of TRAPS, but urticarial or maculopapular rash occur with a similar frequency. Ophthalmological symptoms may be present, such as periorbital edema, conjunctivitis, and uveitis. Patients may report gastrointestinal complaints like nausea, vomiting, and diarrhea, and fatigue [3]. The clinical examination of symptomatic TRAPS patients may reveal cervical lymphadenopathy.

Inflammatory episodes don't necessarily comprise the entire spectrum of symptoms; they may vary in manifestation and severity. Attacks may last up to three weeks, after which symptoms resolve spontaneously. Most patients are free of symptoms in between single bouts of TRAPS, but some present with persistent symptoms that merely decrease in intensity [1]. The average number of episodes per year is 6, but the range of attack frequency is very broad and ranges from 2 to >100 [3]. Flares of inflammation may be triggered by trauma, vaccination, ovulation and menstruation, physical and psychological stress, but most episodes cannot be related to a precise cause.

The presentation and course of the disease should raise suspicion as to a periodic fever syndrome, but there is considerable overlap in the clinical features of TRAPS, familial Mediterranean fever, hyper-IgD syndrome, and other autoinflammatory disorders. Thus, the clinical diagnosis of TRAPS should always be confirmed by means of genetic studies. In case of classical presentation and if corresponding data can be obtained in the familial workup, the sequencing of the TNFRSF1A gene may be carried out in a straightforward approach to diagnosis. Otherwise, further diagnostic measures may be employed to support narrow down the list of differential diagnoses [2]:

• Laboratory analyses typically reveal neutrophilia with a left shift, thrombocytosis, elevated levels of C-reactive protein and serum amyloid proteins. The erythrocyte sedimentation rate is increased. Hyperimmunoglobulinemia may be observed, but autoantibodies are not detected. The inflammatory parameters remain above reference ranges in between symptomatic episodes.
• The histological examination of skin biopsy samples typically reveals monocytic and lymphocytic infiltration around blood vessels. Myalgia is related to chronic fasciitis, and monocytic inflammation can be observed in the respective specimens. Abdominal pain results from peritonitis, and similar findings can be obtained upon the analysis of other serous membranes.
• TRAPS patients do respond to corticosteroids, as do those suffering from hyper-IgD syndrome or periodic fever, aphthous stomatitis, pharyngitis, and adenitis syndrome. Symptoms of familial Mediterranean fever don't improve with corticosteroids [4]. Moreover, colchicine is ineffective in the treatment of TRAPS, and even if inflammatory episodes can initially be contained, patients tend to relapse within months.

Treatment aims at alleviating symptoms and preventing chronic inflammation, which may produce amyloidosis. The suppression of acute symptoms may be achieved by the administration of non-steroidal anti-inflammatory drugs or corticosteroids. Additionally, biological agents may be used to induce a long-term anti-inflammatory state. In this context, inhibitors of tumor necrosis factor α (TNF-α), interleukin-1, and interleukin-6 are most commonly applied.

• With regard to the former, etanercept and infliximab have been studied in several trials. Etanercept functions as a decoy receptor for TNF-α and thus reduces the amount of available cytokine, while infliximab is a monoclonal antibody targeting TNF-α. While partial responses could be achieved with etanercept, results obtained with infliximab were contradictory. What's more, infliximab may produce paradoxical flares of inflammation [3] [5] [6].
• Treatment with anakinra, an antagonist of interleukin-1 receptor, and canakinumab, a monoclonal antibody against interleukin-1β, have yielded more promising results [3]. Several authors have described complete responses in their patients [7] [8] [9].
• Tocilizumab is a monoclonal antibody targeting interleukin-6. It may be effective in patients irresponsive to inhibitors of TNF-α and has been shown to decrease disease activity in isolated cases [10] [11].

Notwithstanding, the number of patients examined in each of the cited studies is very low; some even refer to single cases. The results should thus be interpreted with care, keeping in mind their possibly poor reliability. Given the available data, the following treatment recommendations have been established [2]:

• Non-steroidal anti-inflammatory drugs and corticosteroids constitute the first-line treatment of TRAPS.
• Inhibitors of interleukin-1 are subsequently added, and they may allow for a dose reduction in the aforementioned drugs.
• Inhibitors of TNF-α and interleukin-6 are administered to those responding poorly to other therapies.

Studies regarding the long-term effects of current treatment regimens are yet to be carried out. Patients have repeatedly been described to relapse upon the discontinuation of drug therapy, so they may require lifelong treatment. The latter, however, is associated with high costs.

The early diagnosis and timely treatment of TRAPS is the key to preventing sequelae: Long-standing TRAPS has been known to precipitate amyloidosis of the kidneys, liver, and spleen. Despite therapeutic improvements, up to 10% of TRAPS patients still develop amyloidosis. The risk of amyloidosis is particularly high if the underlying gene defect disrupts the cysteine-rich extracellular domains of the TNF-α receptor 1 protein (TNFR1). TRAPS may also be associated with an increased risk of cardiovascular disease, namely myocardial infarction and arterial thrombosis [2]. Macrophage activation syndrome is another possible complication of the disease but has been reported in isolated cases only [12].

Due to the rarity of complications other than amyloidosis, the individual patient's risk of developing this condition is generally considered the determinant of the long-term outcome.

Mutations in the TNFRSF1A gene, which encodes for tumor necrosis factor receptor 1, can be identified in the majority of TRAPS patients. To date, more than 150 mutations have been discovered. TNFRSF1A encodes for the TNFR1 protein, which promotes nuclear factor-κB signaling and the apoptosis pathway upon stimulation by TNF-α. TNFR1 comprises cysteine-rich extracellular domains and an intracellular death domain, and TRAPS is generally related to alterations in the extracellular domain [2] [13].

Both autosomal dominant and autosomal recessive patterns of inheritance have been described, and the penetrance of pathogenic traits is variable. Penetrance may depend on the underlying mutation, with mutations affecting cysteine-rich extracellular domains resulting in higher penetrance. These same mutations have been associated with an early onset of symptoms, a more severe phenotype, longer duration of episodes, and decreased frequency of bouts per year [2]. Among the more common mutations related to low penetrance and a mild phenotype is TNFRSF1A variant R92Q [14].

While initially observed in patients of Irish and Scottish descent, TRAPS has now been described in different ethnicities, including African Americans, Latin Americans, Mediterranean people, and distinct European folks. Males and females are affected equally [4] [14]. Reliable data regarding the incidence and prevalence of TRAPS cannot be provided, but the overall incidence of hereditary autoinflammatory disorders has been estimated at 3 per million person-years. While familial Mediterranean fever accounts for the vast majority of these cases, a very small portion may correspond to TRAPS [15].

TNFR1 is trafficked to the cell surface, where it assumes its function as a receptor of TNF-α. Upon the binding of its agonist, TNFR1 undergoes trimerization and activation. It is involved in numerous signaling cascades that regulate cell survival and apoptosis, and inflammation. In detail, pro-inflammatory events mediated by TNFR1 comprise the production of cytokines like interleukin-1 and interleukin-6, the induction of reactive oxygen species and NO, and the upregulation of adhesion molecule expression. Proteolytic cleavage of membrane-bound TNFR1 is catalyzed by metalloproteases and results in receptor shedding and the rapid reduction in the number of available receptors. This same process renders soluble TNFR1, which interacts with free TNF-α and thus competes with membrane-bound receptors for the agonist, thereby exerting anti-inflammatory effects.

Mutations in the TNFRSF1A gene that predispose to TRAPS may interfere with the aforedescribed mechanisms at different points of the cascade:

• Intracellular trafficking of TNFR1 may be disturbed. The misfolded protein remains in the endoplasmatic reticulum and induces the constitutive expression of other pro-inflammatory cytokines [1].
• Deficiencies in the induction of programmed cell death may result in the prolonged survival of inflammatory cells.
• Mutant TNFR1 may not be cleaved by the respective protease and may thus accumulate in the cell membrane.

Families known to harbor mutations predisposing to TRAPS may benefit from genetic counseling. Carriers may be identified before the onset of symptoms, and even before birth.

Autoinflammatory disorders are characterized by recurrent episodes of fever and localized inflammation. Autoantibodies cannot be detected, and there is a tendency towards familial clustering. These disorders are currently grouped into four classes, namely hereditary periodic fever syndromes, cryopyrin-associated periodic syndromes, pediatric systemic granulomatosis, and other hereditary systemic autoinflammatory diseases. TRAPS belongs to the first group [1].

TRAPS was first described in 1982, when recurrent episodes of fever, rash, myalgia, and abdominal pain were observed in a large Irish family. The authors of the original paper referred to the disease as "familial Hibernian fever" [16]. It was not until 1999, that the condition could be linked to germline mutations affecting TNFR1 [13]. McDermott and colleagues have speculated the autoinflammatory phenotype to result from impaired downregulation of membrane-bound TNFR1 and diminished shedding of the receptor, and these hypotheses are still valid today. Yet, considerable knowledge gaps remain regarding the pathogenesis of the disease as well as genotype-phenotype correlations.

What's more, mutations of the TNFRSF1A gene have also been related to multiple sclerosis, and patients carrying TNFRSF1A variant R92Q may develop symptoms of either disease [17]. The involvement of additional genetic and/or environmental factors has been discussed in this context, but conclusive results have yet to be provided.

Tumor necrosis factor receptor 1-associated periodic syndrome (TRAPS) is a hereditary disease. It is caused by mutations in the TNFRSF1A gene, which encodes for the receptor of tumor necrosis factor-α. The latter is commonly referred to as TNF-α and plays a key role in inflammation. Carriers of the respective mutations are predisposed to inflammation and suffer from recurrent episodes of fever, skin rash, joint and muscle pain. Patients may also experience gastrointestinal disorders like nausea, vomiting, diarrhea, and abdominal pain. These symptoms frequently develop without an apparent cause, last for several days and up to three weeks, and resolve spontaneously. Most patients are free of symptoms in between single attacks, but some continue to have mild complaints.

Disease onset typically occurs in childhood but may be delayed until adulthood. Family members of TRAPS patients may be identified as carriers of pathogenic variants of TNFRSF1A and may thus be diagnosed before the manifestation of symptoms, possibly before birth. Otherwise, the diagnosis relies on a high index of suspicion. The presentation and course of the disease should raise suspicion as to a periodic fever syndrome, and the long-lasting bouts of inflammation may hint at TRAPS. In any case, genetic studies have to be carried out to confirm the diagnosis.

TRAPS patients are provided symptomatic treatment. Acute symptoms may be alleviated by non-steroidal anti-inflammatory drugs or corticosteroids, whereas long-term treatment also includes modulators of inflammation such as inhibitors of interleukin-1, interleukin-6, and TNF-α. Relapses may occur upon the discontinuation of therapy, so patients may require lifelong treatment. Further research is required, though, to broaden the spectrum of therapeutic options and to provide additional data on the long-term effects of current treatment regimens.

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