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

  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]

  Keywords Endoplasmic Reticulum Stress Familial Mediterranean Fever Endoplasmic Reticulum Stress Response Periodic Fever Periodic Fever Syndrome Introduction The TNF-receptor associated periodic syndrome (TRAPS) is a dominantly inherited periodic fever [doi.org]

  The frequency of the episodes varies greatly among affected individuals; fevers can occur anywhere between every 6 weeks to every few years. Some individuals can go many years without having a fever episode. [ncbi.nlm.nih.gov]

  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]

  Prognosis With age, fever attacks may decrease in intensity and a more chronic and fluctuating course can be observed. Secondary amyloidosis complicates the course of the disease. [orpha.net]

• Inflammation

  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]

  Protein aggregates constantly activate these alternative pathways of inflammation, leading to excessive inflammation in people with the disease. [ivami.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]

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

• 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]

  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]

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

  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]

  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]

  […] 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]

  Though the father and children had some phenotypic variability, the febrile periods were > 1 week long in all of them, they had consistently 2 to 3 episodes a year, and they all lacked lymphadenopathies and cutaneous or ophthalmologic manifestations, [hindawi.com]

• Chills

  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]

  Specific Code Applicable To Arthrosis NOS Arthritis NOS Osteoarthritis NOS in (due to) Mediterranean fever, familial M04.1 - see also subcategory M14.8- Deficiency, deficient mevalonate kinase M04.1 Fever (inanition) (of unknown origin) (persistent) (with chills [icd10data.com]

  Formerly known as Familial Hibernian fever, Tumor Necrosis Factor Receptor Associated Periodic Syndrome (TRAPS) is a rare, genetic disease that causes recurrent episodes of fever that typically last more than one week and are associated with chills and [rheumatology.org]

  […] for symptoms of TB during treatment with ILARIS check you for symptoms of any type of infection before, during, and after treatment with ILARIS Tell your healthcare provider right away if you have any symptoms of an infection such as fever, sweats or chills [ilaris.com]

• Nasal Ulcer

  The patient denied recent travel, oral/nasal ulcers, joint swelling, morning stiffness, Raynaud’s, photosensitivity, malar rash, or sicca symptoms. A recent short course of oral glucocorticoids helped with her pleuritic pain. [ncbi.nlm.nih.gov]

• 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]

  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]

  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]

• 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]

  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]

  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]

• 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]

  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]

  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]

  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]

  […] 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]

  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]

• 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]

  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]

  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]

• Erythema

  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]

  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]

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

• Periorbital Edema

  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]

• Eye Pain

  pain 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]

• 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]

  The most distinctive features of an attack are fever and migratory myalgia and swelling in the extremities. The overlying skin is red and tender. [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]

  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]

• 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]

  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]

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

• Malar Rash

  The patient denied recent travel, oral/nasal ulcers, joint swelling, morning stiffness, Raynaud’s, photosensitivity, malar rash, or sicca symptoms. A recent short course of oral glucocorticoids helped with her pleuritic pain. [ncbi.nlm.nih.gov]

• 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]

  Affects 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]

  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]

  Symptoms during attacks usually include: Typical rash in TRAPS, affecting the arm Fever lasting around 1 to 4 weeks abdominal pain joint or muscle aches and swelling rash more rarely there may also be: headache chest pain enlarged glands in the neck painful [amyloidosis.org.uk]

  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]

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.

• Normocytic Normochromic Anemia

  On this first consultation, the patient provided blood and urine workup from 3 months earlier that documented normocytic, normochromic anemia (Hb 12 g/dL), an elevation of creatinine and BUN to 1.9 mg/dL and 66 mg/dL, respectively, and proteinuria of [hindawi.com]

• Trypanosoma Cruzi

  Chagas disease (American trypanosomiasis), conserved biosystem (from KEGG) Chagas disease (American trypanosomiasis), conserved biosystem Trypanosoma cruzi is an intracellular protozoan parasite that causes Chagas disease. [ncbi.nlm.nih.gov]

• Neurofibrillary Tangle

  AD is associated with senile plaques and neurofibrillary tangles (NFTs). Amyloid-b... [ncbi.nlm.nih.gov]

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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