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.

• Fever

  Other cases result from new mutations in the gene and occur in people with no history of the disorder in their family. autosomal dominant familial periodic fever familial Hibernian fever FPF TNF receptor-associated periodic fever syndrome TRAPS Aganna [ghr.nlm.nih.gov]

  Drenth JPH, van Der Meer JW (2000) Periodic fevers enter the era of molecular diagnosis. BMJ 320:1091–1092 PubMed CrossRef Google Scholar 4. [springerlink.com]

  Hereditary fever syndromes have to be considered in case of chronic unexplained inflammation even if fever is no presenting symptom. [ncbi.nlm.nih.gov]

  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". [symptoma.com]

• Inflammation

  The clumps of protein constantly activate these alternative inflammation pathways, leading to excess inflammation in people with TRAPS. [ghr.nlm.nih.gov]

  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. [symptoma.com]

  Etiology Mutations in the TNFRSF1A (12p13.2) gene encoding TNFR1, that plays a key role in systemic inflammation, have been shown to underlie this condition. [orpha.net]

  It is characterized by recurrent episodes of fever and inflammation in different regions of the body. The main clinical manifestations are myalgia, migratory erythematous rash, periorbital edema, and abdominal pain. [actasdermo.org]

• Pain

  pain, and arthralgia.Some patients have severe abdominal pain leading to abdominal surgery. [kyushu-u.pure.elsevier.com]

  The characteristic features include recurrent fevers of varying duration, abdominal pain, and recurrent cutaneous and synovial inflammation. [indianpediatrics.net]

  Other symptoms of TRAPS may include headache, abdominal pain, diarrhea or constipation, nausea, painful conjunctivitis, periorbital edema, joint pain, rash, and testicular pain. Males are prone to develop inguinal hernias. [msdmanuals.com]

  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. [symptoma.com]

  […] with redness, pleuritic chest pains, intermittent abdominal pain, diffuse myalgias and achiness on the left side of her face, fatigue, hair loss, and unintentional weight loss of 30 pounds. [ncbi.nlm.nih.gov]

• Lymphadenopathy

  Tumor-necrosis-factor Receptor Associated Periodic fever Syndrome (TRAPS) is characterized by periodic fever, cutaneous rash, conjunctivitis, lymphadenopathy, abdominal pain, myalgia and arthralgia [1]. [indianpediatrics.net]

  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. [symptoma.com]

  […] inflammation 0001369 Constipation 0002019 Erythema 0010783 Intestinal obstruction Bowel obstruction Intestinal blockage [ more ] 0005214 Leukocytosis Elevated white blood count High white blood count Increased blood leukocyte number [ more ] 0001974 Lymphadenopathy [rarediseases.info.nih.gov]

• Asymptomatic

  Treatment with colchicine brought only temporary improvement including an asymptomatic period of 13 weeks. Additional symptoms such as abdominal pain, arthralgia, and conjunctivitis developed in time. [archivesofrheumatology.org]

  Family history is usually positive in TRAPS; although some carriers may be entirely asymptomatic [4]. [ncbi.nlm.nih.gov]

  Although most TRAPS‐associated mutations are fully penetrant, 2 TNFRI variants, P46L and R92Q, have also been identified in asymptomatic family members and at a low frequency in healthy populations. [onlinelibrary.wiley.com]

  Non-familial cases have been reported and genetic studies of relatives of affected individuals have detected asymptomatic carriers, suggesting variable penetrance. [dermnetnz.org]

• Abdominal Pain

  pain, and arthralgia.Some patients have severe abdominal pain leading to abdominal surgery. [kyushu-u.pure.elsevier.com]

  Patients suffer from periodic bouts of severe abdominal pain, localised inflammation, migratory rashes, and fever. More than 40 individual mutations have been identified, all of which occur in the extracellular domain of TNFR1. [ncbi.nlm.nih.gov]

  Abdominal pain due to serositis is seen in 92% patients, which may sometimes lead to unnecessary abdominal surgery [4]. Ocular symptoms include periorbital edema, conjunctivitis, uveitis and iritis. [indianpediatrics.net]

  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. [symptoma.com]

• Vomiting

  Patients may report gastrointestinal complaints like nausea, vomiting, and diarrhea, and fatigue. The clinical examination of symptomatic TRAPS patients may reveal cervical lymphadenopathy. [symptoma.com]

  The fever is typically accompanied by gastrointestinal disturbances (abdominal pain, vomiting, diarrhoea), painful red skin rash, muscle pain and swelling around the eyes. Impaired kidney function can be observed in the late phase of the disease. [printo.it]

  TRAPS flares are associated with the following symptoms:[4,5,7] Persistent fever Abdominal and/or chest pain Nausea, vomiting, diarrhoea or constipation Painful, often migrating red rash on the upper body and/or arms/legs Swollen eyes (periorbital oedema [periodicfevers.com]

  Abdominal pain with nausea, vomiting, and diarrhea are common, as are red, swollen eyes. Other important features include chest pain due to inflammation of the membrane surrounding the lungs or heart. [rheumatology.org]

  These febrile periods were often accompanied by headaches or myalgia that was focal and migratory, but he denied pharyngitis, skin rashes or urticaria, aphthous ulcers, abdominal pain, arthritis, or vomiting. [hindawi.com]

• Diarrhea

  Patients may report gastrointestinal complaints like nausea, vomiting, and diarrhea, and fatigue. The clinical examination of symptomatic TRAPS patients may reveal cervical lymphadenopathy. [symptoma.com]

  Tell your healthcare provider right away if you have any symptoms of an infection such as fever, sweats or chills, cough, flu-like symptoms, weight loss, shortness of breath, blood in your phlegm, sores on your body, warm or painful areas on your body, diarrhea [ilaris.com]

  Other symptoms of TRAPS may include headache, abdominal pain, diarrhea or constipation, nausea, painful conjunctivitis, periorbital edema, joint pain, rash, and testicular pain. Males are prone to develop inguinal hernias. [msdmanuals.com]

  Abdominal pain with nausea, vomiting, and diarrhea are common, as are red, swollen eyes. Other important features include chest pain due to inflammation of the membrane surrounding the lungs or heart. [rheumatology.org]

  Case presentation The patient presented at 7 months of age with seven days of fever, vomiting, diarrhea, and faint erythematous papular rash. [bmcpediatr.biomedcentral.com]

• Constipation

  Other symptoms of TRAPS may include headache, abdominal pain, diarrhea or constipation, nausea, painful conjunctivitis, periorbital edema, joint pain, rash, and testicular pain. Males are prone to develop inguinal hernias. [msdmanuals.com]

  TRAPS flares are associated with the following symptoms:[4,5,7] Persistent fever Abdominal and/or chest pain Nausea, vomiting, diarrhoea or constipation Painful, often migrating red rash on the upper body and/or arms/legs Swollen eyes (periorbital oedema [periodicfevers.com]

  Swelling or irritation of membrane around heart 0001701 Recurrent fever Episodic fever Increased body temperature, episodic Intermittent fever [ more ] 0001954 Skin rash 0000988 30%-79% of people have these symptoms Arthritis Joint inflammation 0001369 Constipation [rarediseases.info.nih.gov]

  […] from 2 days up to more than one month, usually 1-3 weeks Recurs 2-6 times per year Does not respond to aspirin or paracetamol Abdominal pain Affects 90% Due to sterile peritonitis Pain may be described as colicky Associated loss of appetite, vomiting, constipation [dermnetnz.org]

• Nausea

  Patients may report gastrointestinal complaints like nausea, vomiting, and diarrhea, and fatigue. The clinical examination of symptomatic TRAPS patients may reveal cervical lymphadenopathy. [symptoma.com]

  Other symptoms of TRAPS may include headache, abdominal pain, diarrhea or constipation, nausea, painful conjunctivitis, periorbital edema, joint pain, rash, and testicular pain. Males are prone to develop inguinal hernias. [msdmanuals.com]

  TRAPS flares are associated with the following symptoms:[4,5,7] Persistent fever Abdominal and/or chest pain Nausea, vomiting, diarrhoea or constipation Painful, often migrating red rash on the upper body and/or arms/legs Swollen eyes (periorbital oedema [periodicfevers.com]

  As well as fever other associated symptoms are headache, abdominal pain, rash, nausea, painful conjunctivitis, and joint pain. Patients who develop amyloidosis of the kidney have a worse prognosis compared to others. [drugs.com]

  Abdominal pain with nausea, vomiting, and diarrhea are common, as are red, swollen eyes. Other important features include chest pain due to inflammation of the membrane surrounding the lungs or heart. [rheumatology.org]

• Jaundice

  Furthermore, while three days old, the infant experienced an afebrile inflammatory attack characterized by jaundice, poor feeding, lethargy, urticarial rash, increased markers of inflammation (C-reactive protein of 47 mg/L, procalcitonin of 0.5 ng/mL, [archivesofrheumatology.org]

• Erythema

  Most patients developed rash (erythema) (84.6 %) and arthralgia (73.3 %), and half suffered frommyalgia (54.5 %) and abdominal pain (50.0 %). Although one-half of the patients suffered from abdominal pain, none underwent surgery. [kyushu-u.pure.elsevier.com]

  We report a 16-year-old female patient, who suffered from periodic erythema and myositis/fasciitis. She experienced at least nine attacks of dermatitis and myositis, while no fever episodes were noted over a 3-year period. [ncbi.nlm.nih.gov]

  Skin manifestations include centrifugal, migratory, erysepela-like erythema, edematous plaques and urticarial lesions. [orpha.net]

• Periorbital Edema

  The main clinical manifestations are myalgia, migratory erythematous rash, periorbital edema, and abdominal pain. [actasdermo.org]

  Eye involvement can manifest in the form of conjunctivitis, periorbital edema (highly specific feature for TRAPS) or uveitis (see this term). Serosal inflammation (pleuritis, peritonitis) is common. [orpha.net]

  Affected individuals may also experience puffiness or swelling in the skin around the eyes (periorbital edema); joint pain; and inflammation in various areas of ... the body including the eyes, heart muscle, certain joints, throat, or mucous membranes [ncbi.nlm.nih.gov]

• Arthritis

  […] and Rheumatism Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, MD, USA Ivona Aksentijevich & Daniel L Kastner Department of Medicine, Division of Infectious Diseases and AIDS and Eijkman-Winkler Institute, University [nature.com]

  Arthritis Res Ther. 2007;9(4):217. Review. Masson C, Simon V, Hoppé E, Insalaco P, Cissé I, Audran M. [ghr.nlm.nih.gov]

  Arthritis Rheum 43:1535–1542 PubMed CrossRef Google Scholar 11. [springerlink.com]

  Arthritis Rheum 2002; 46:2181–8. Google Scholar | Crossref | Medline 3. D'Osualdo, A, Ferlito, F, Prigione, I. [journals.sagepub.com]

• Myalgia

  Notably, the patient's 26-year-old nephew had experienced similar symptoms since childhood, including migratory myalgias, cyclical chills, and night sweats. [ncbi.nlm.nih.gov]

  Tumor necrosis factor receptor-associated periodic syndrome (TRAPS) is a dominantly inherited autoinflammatory syndrome that is characterized by recurrent episodes of fever attacks associated with rashes, abdominal pain, myalgia, conjunctivitis, chest [kyushu-u.pure.elsevier.com]

  Clinically, episodes of severe myalgia, arthralgia/arthritis, sterile peritonitis, scrotal inflammation, serositis, migratory rash, conjunctivitis, and recurrent fever are characteristic. [jrheum.org]

  It has been reported that cutaneous lesions were commonly associated with underlying myalgia.3 In many cases, the myalgia moves down the extremity in conjunction with the skin lesions, affecting different muscle groups and limiting joint movement during [tandfonline.com]

• Arthralgia

  Most patients developed rash (erythema) (84.6 %) and arthralgia (73.3 %), and half suffered frommyalgia (54.5 %) and abdominal pain (50.0 %). Although one-half of the patients suffered from abdominal pain, none underwent surgery. [kyushu-u.pure.elsevier.com]

  Clinically, episodes of severe myalgia, arthralgia/arthritis, sterile peritonitis, scrotal inflammation, serositis, migratory rash, conjunctivitis, and recurrent fever are characteristic. [jrheum.org]

  Recurrent fever, abdominal pain, myalgia, and arthralgia are the most common manifestations of TRAPS. [genome.jp]

  Abdominal pain and arthralgias are frequent symptoms. Secondary amyloidosis with renal and hepatic manifestations may eventually develop. An increased risk of atherosclerosis and acute myocardial infarction has been noted. [orpha.net]

• Testicular Pain

  Other symptoms of TRAPS may include headache, abdominal pain, diarrhea or constipation, nausea, painful conjunctivitis, periorbital edema, joint pain, rash, and testicular pain. Males are prone to develop inguinal hernias. [msdmanuals.com]

  40% Due to sterile pleuritis or pericarditis Testicular pain Occasional Lymph node swelling Not common Inguinal hernias are common in affected males. [dermnetnz.org]

  Additional symptoms that have been reported in males with TRAPS include testicular pain and a higher rate of inguinal hernia than is found in the general population. [rarediseases.org]

  […] conjunctivitis.1,3,5,12 Histologically, skin lesions in TRAPS are characterized by a perivascular dermal infiltrate of lymphocytes and monocytes.3 Other clinical symptoms that may be present in TRAPS include ptosis, calf pain, testicular pain, arthralgias [tandfonline.com]

• Headache

  In contrast, only a small percentage of patients suffered from chest pain (20.0 %), conjunctivitis (20.0 %), and headache (10.0 %). Almost all cases (95.7 %) concerned patients whose relatives suffered from periodic fever. [kyushu-u.pure.elsevier.com]

  Migraine headache Migraine headaches [ more ] 0002076 Myositis Muscle inflammation 0100614 Paresthesia Pins and needles feeling Tingling [ more ] 0003401 Periorbital edema 0100539 Peritonitis 0002586 Recurrent pharyngitis Recurrent sore throat 0100776 [rarediseases.info.nih.gov]

  This patient presented to our outpatient clinic with uncontrolled hypertension (195/110 mmHg), leg edemas that extended to the lower thighs, and complaints of fatigue and headaches. [hindawi.com]

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.

• Colitis

  Increased risk of developing Crohn's disease or ulcerative colitis in 17 018 patients while under treatment with anti‐TNFα agents, particularly etanercept, for autoimmune diseases other than inflammatory bowel disease. [labtestsonline.it]

  These medications can be used to treat: Rheumatoid arthritis Psoriatic arthritis Juvenile arthritis Crohn's disease Ulcerative colitis Ankylosing spondylitis Psoriasis Rheumatoid arthritis patients who have not responded sufficiently to TNF inhibitors [webmd.com]

  Ruther U, Nunnensiek C, Muller HA et al (1998) Interferon alpha (ifn alpha 2a) therapy for herpes virus-associated inflammatory bowel disease (ulcerative colitis and crohn’s disease). Hepatogastroenterology 45:691–699 PubMed Google Scholar 44. [link.springer.com]

  These animals develop clinical signs of arthritis and colitis. 21 However, when this modified TNF transgene is crossed into TNF-R2-deficient mice, a near to normal phenotype is observed, pointing to a significant contribution of this receptor for the [nature.com]

• Hepatocellular Carcinoma

  Cancer, Epithelial Ovarian Cancer, Esophageal Cancer, Esophageal Squamous Cell Carcinoma (ESCC), Fallopian Tube Cancer, Gastric Cancer, Hepatocellular Carcinoma, Lymphoma, Metastatic Colorectal Cancer, Metastatic Melanoma, Metastatic Renal Cell Carcinoma [m.giikorea.co.kr]

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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