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Tumor necrosis factor receptor-1 associated periodic syndrome (TRAPS)

Tumor necrosis factor receptor-1 associated periodic syndrome (TRAPS)
Literature review current through: Jan 2024.
This topic last updated: Oct 03, 2023.

INTRODUCTION — The best-characterized autoinflammatory diseases are relatively rare but florid conditions that arise from pathogenic variants in single genes. The prototypical autoinflammatory disorders are the periodic fever syndromes. One of these disorders, the tumor necrosis factor (TNF) receptor-1 associated periodic syndrome (TRAPS; MIM #142680, formerly known as familial Hibernian fever), is reviewed here. An overview of autoinflammatory diseases is presented separately. (See "The autoinflammatory diseases: An overview".)

Detailed descriptions of the clinical manifestations, diagnosis, and treatment of the major autoinflammatory diseases are presented elsewhere. Classification and genetic testing for inborn errors of immunity are also discussed in detail separately:

(See "Inborn errors of immunity (primary immunodeficiencies): Classification".)

(See "Genetic testing in patients with a suspected primary immunodeficiency or autoinflammatory syndrome".)

(See "Autoinflammatory diseases mediated by interferon production and signaling (interferonopathies)".)

(See "Autoinflammatory diseases mediated by inflammasomes and related IL-1 family cytokines (inflammasomopathies)".)

(See "Autoinflammatory diseases mediated by NFkB and/or aberrant TNF activity".)

(See "Autoinflammatory diseases mediated by miscellaneous mechanisms".)

(See "Deficiency of adenosine deaminase 2 (DADA2)".)

(See "Cryopyrin-associated periodic syndromes and related disorders".)

(See "Familial Mediterranean fever: Epidemiology, genetics, and pathogenesis" and "Clinical manifestations and diagnosis of familial Mediterranean fever" and "Management of familial Mediterranean fever".)

(See "Hyperimmunoglobulin D syndrome: Pathophysiology" and "Hyperimmunoglobulin D syndrome: Clinical manifestations and diagnosis" and "Hyperimmunoglobulin D syndrome: Management".)

AUTOIMMUNE VERSUS AUTOINFLAMMATORY DISEASE — Many well-known disorders of immune excess result from autoimmunity, a failure of self/nonself discrimination by T and B cells, the effector cells of the adaptive arm of the immune system. (See "Overview of autoimmunity".)

A second category of immune-mediated disease results from inappropriate activation of antigen-independent inflammatory mechanisms. This group of disorders has been termed "autoinflammatory diseases."

Autoinflammatory diseases prominently involve cells of the innate immune system as well as the mediators associated with these cells. Thus, autoinflammatory diseases are broadly considered to represent primary diseases of innate immunity, in contrast to the autoimmune diseases that result from aberrant adaptive or acquired immunity. However, this separation is far from absolute [1].

EPIDEMIOLOGY — TRAPS is a rare disorder, with a prevalence of approximately one per million [2-4]. While originally described in an Irish (Hibernian) kindred, cases have since been reported in many ethnic groups. Thus, ancestry plays no role in the assessment of the likelihood that a patient has this disorder.

GENETICS — TRAPS is inherited in an autosomal dominant fashion with incomplete penetrance [4]. The genetic defect in TRAPS resides in the gene that encodes the 55 kDa receptor for TNF, TNFR1 (TNF receptor superfamily member 1A [TNFRSF1A gene]; MIM *191190) [2]. In some cases, the pathogenic variants result in impaired shedding of this receptor. Some TNFRSF1A variants have high penetrance (ie, most persons with the variant develop the disease), while others have appreciable prevalence in healthy individuals. As an example, the arginine-to-glutamine missense mutation at amino acid 92 (R92Q mutation) is found in 2 percent of the White population, making it unlikely to be causative in isolation, but is nevertheless common among patients with a TRAPS-like illness that is usually milder and without amyloidosis [4-6]. The P46L and T61I are common variants, particularly in Northern/Western Africa and in Japan, respectively, but may occasionally be associated with TRAPS symptomatology [4,7,8].

There is no exact correlation between genetic variant and clinical phenotype. However, the risk of secondary (inflammatory or amyloid A [AA]) amyloidosis is largely restricted to patients bearing pathogenic and likely pathogenic variants affecting certain cysteine residues. Classic presentation of intermittent fevers, rash, and abdominal pain as well as response to interleukin (IL) 1 blockade is also most common in this group [9]. For patients with variants of unknown significance or other variants, fulfilment of Eurofever criteria for TRAPS in the absence of a confirmatory variant (at least two of the following: duration of episodes ≥7 days, myalgia, migratory rash, periorbital edema) predicted better therapeutic response to IL-1 blockade [9].

PATHOGENESIS — The pathogenesis of human TRAPS remains uncertain [10]. Impaired shedding of TNFR1 eliminates an endogenous antagonist to circulating TNF. However, other mechanisms are probably more important since patients may have normal levels of soluble TNF receptor. An excess of retained surface TNFR1 may result in enhanced susceptibility to TNF [2,11]. Conversely, mutant receptor may bind TNF less efficiently, leading to impaired TNF-driven apoptosis [12,13]. Finally, mutant TNFR1 may misfold and/or traffic aberrantly within the cell [14-17]. These events can trigger an unfolded protein response (UPR; a cellular stress response associated with accumulation of unfolded or misfolded protein in the endoplasmic reticulum) or initiate TNF-independent signaling within the cell mediated by enhanced production of mitochondrial-derived reactive oxygen species that disturb intracellular signaling pathways. Thus, despite beginning with a defect in the TNF system, TRAPS appears to be mediated by other proinflammatory mediators as well, including interleukin (IL) 1 beta [14,18]. The resulting pivotal role of IL-1 beta is evident in the success of clinical antagonism of this cytokine [19].

CLINICAL MANIFESTATIONS

Age at presentation — Most patients present in the first decade of life (median 4.3 years in the largest series of 158 patients), but approximately 10 percent present over the age of 30 years [3,4].

Fever — Recurrent fevers >38°C/100.4°F over months or years in the absence of associated viral or bacterial infections are characteristic of TRAPS, occurring in at least 88 percent of patients [3,4,8,20]. Febrile episodes every five to six weeks are typical, though clockwork periodicity is lacking. Precipitating factors are generally not identified, though some patients or caregivers observe that physical and emotional stress may tend to trigger attacks. Fever and associated symptoms commonly last at least five days and often continue for more than two weeks.

Other features — Other clinical features include [3,4,8,9,20]:

Myalgia and limb pain, sometimes migratory (59 to 85 percent)

Abdominal symptoms (36 to 74 percent), including pain and vomiting (18 percent)

Rash (55 to 63 percent)

Lymphadenopathy (25 percent)

Headache (20 to 25 percent)

Chest pain (14 to 25 percent)

Conjunctivitis (18 to 22 percent)

Periorbital edema (9 to 20 percent)

Pharyngitis, with or without aphthae (9 to 18 percent)

Monoarticular arthritis (13 percent)

Hepatomegaly and/or splenomegaly (5 to 10 percent)

Impaired fertility and/or recurrent miscarriages (3 percent)

Characteristically, the rash presents as single or multiple erythematous patches (picture 1) that may spread distally down an extremity over time [21].

Presentation as recurrent pericarditis has also been reported [22].

Subacute presentation — A subacute presentation, reported in some adult patients, is characterized by myalgias, fatigue, and persistent elevation of inflammatory markers [4,23]. Common variants with incomplete penetrance (eg, R92Q) may be overrepresented in this group, rendering it especially important to confirm systemic inflammation to avoid confusion with fibromyalgia and other causes of chronic pain and fatigue. (See "Clinical manifestations and diagnosis of fibromyalgia in adults", section on 'Clinical manifestations'.)

Secondary (AA) amyloidosis — Approximately 10 to 15 percent of patients develop clinical manifestations of secondary amyloidosis, also called AA amyloidosis since the deposited protein is serum amyloid A [3,4,24-28]. AA amyloidosis may be diagnosed first, with TRAPS identified subsequently [29]. This form of amyloidosis primarily involves the kidney and is a potentially life-threatening complication of TRAPS. However, the liver, thyroid, heart, and other organs may be affected. The signs and symptoms of amyloidosis with TRAPS are similar to those observed with secondary amyloidosis in other disorders. Proteinuria or signs/symptoms of nephrotic syndrome suggest amyloidosis. Other suggestive clinical and laboratory features include hepatomegaly, waxy skin and easy bruising, enlarged muscles, heart failure and cardiac conduction abnormalities, peripheral and/or autonomic neuropathy, and impaired coagulation. (See "Overview of amyloidosis", section on 'Clinical manifestations' and "Renal amyloidosis".)

The risk of secondary (AA) amyloidosis is increased among patients with pathogenic variants affecting cysteine residues (eg, C33Y), probably reflecting the higher cumulative inflammatory burden associated with these variants [4,24]. These cysteines form intramolecular disulfide bonds that help to maintain the three-dimensional structure of TNFR1. Since 15 to 24 percent of patients with cysteine variants, or with the variant T50M, develop amyloidosis compared with only 2 to 7 percent of patients with other variants [3,4,24], the identification of an individual patient's variant may drive therapeutic decisions. In particular, the risk of amyloidosis in patients with R92Q appears to be very low (0 of 54 in one series) [4]. (See 'Management' below.)

LABORATORY FINDINGS

Inflammatory markers and autoantibodies — Laboratory investigation reveals elevation of inflammatory markers including the erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP). Such markers are particularly elevated during attacks but commonly remain modestly elevated even during asymptomatic periods. Autoantibodies, such as rheumatoid factor and antinuclear antibodies (ANA), are usually absent or are present at low titer [3].

Findings associated with secondary amyloidosis — Patients with involvement of the kidney and other organs with secondary amyloidosis may have proteinuria, kidney insufficiency, and dysfunction of involved organs. This is discussed separately. (See "Overview of amyloidosis", section on 'Clinical manifestations'.)

Histology — Biopsy of involved skin reveals superficial and deep infiltration by lymphocytes and monocytes [21]. A monocytic fasciitis, rather than a true myositis, appears to be responsible for myalgia. Serum levels of muscle enzymes are normal [3].

In patients with secondary amyloidosis, the serum amyloid A protein deposits appear as amorphous hyaline material on light microscopy. (See "Overview of amyloidosis", section on 'Selection of biopsy site'.)

DIAGNOSIS — A diagnosis of TRAPS should be entertained only after bacterial and other infectious and neoplastic causes of recurrent fever have been excluded (see 'Differential diagnosis' below). The evaluation then proceeds with an attempt to identify a clinical pattern consistent with one of the major autoinflammatory disorders. Validated criteria have been developed for the classification of the major periodic fever syndromes (table 1) [30]. The diagnosis of TRAPS is suggested by a history of recurrent fever and one or more of the other clinical features noted above. There are no specific laboratory tests, outside of genetic testing, that can establish the diagnosis.

Particular hallmarks of TRAPS include the protracted duration of attacks (at least six days, though typically longer), prominent myalgias, migratory rash, and periorbital edema [3,30]. Family history is commonly positive, although some carriers of TRAPS variants may be entirely asymptomatic.

The diagnosis of TRAPS is confirmed by genetic testing for disease-associated pathogenic variants in the TNFR1 gene (TNFRSF1A). Testing is available commercially. A list of TNFRSF1A mutations is available in published references [9] and in the online Infevers database. Variants are classified as pathogenic, likely pathogenic, of unknown significance, not classified, likely benign, and benign. While R92Q (also called R121Q) is believed to represent a truly causative variant in some patients, it is sufficiently common in the healthy population that other possibilities in the differential diagnosis should still be excluded before making a final diagnosis. Some experts regard the R92Q syndrome as sufficiently different from that resulting from other TNFRSF1A mutations that they consider symptomatic patients bearing this variant to have a disease distinct from TRAPS [6,23,31]. Somatic mosaicism resulting in symptomatic disease has been reported [32,33]. (See 'Genetics' above.)

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of recurrent fever is broad, including autoimmune diseases, other autoinflammatory diseases, and several other disorders.

Recurrent fevers due to bacterial and other infectious and neoplastic causes — As previously mentioned, a diagnosis of TRAPS should be entertained only after bacterial and other infectious and neoplastic causes of recurrent fever have been excluded. (See appropriate topic reviews.)

In addition, patients with TRAPS and other periodic fevers are often evaluated initially for fever of unknown origin (FUO). General approaches to the child and to the adult with FUO are presented separately. (See "Fever of unknown origin in children: Evaluation", section on 'Overview of evaluation' and "Fever of unknown origin in children: Evaluation", section on 'Initial evaluation' and "Fever of unknown origin in adults: Evaluation and management".)

Other immune-mediated diseases — Systemic lupus erythematosus (SLE) and Still's disease in children (systemic juvenile idiopathic arthritis) and adults (adult-onset Still's disease) can also present with fever, joint pain, and skin rash. Unlike TRAPS, patients with SLE almost invariably have antinuclear antibodies (ANA) and often have hypocomplementemia, glomerulonephritis, and cytopenias, which are not seen with TRAPS. Inflammatory bowel disease and vasculitis can present with fever and prominent systemic inflammation. None of these conditions typically present with stereotyped episodes of recurrent inflammation over the course of months or years. (See "Childhood-onset systemic lupus erythematosus (SLE): Clinical manifestations and diagnosis" and "Clinical manifestations and diagnosis of systemic lupus erythematosus in adults".)

Other autoinflammatory diseases — Certain clinical features help to distinguish TRAPS from other autoinflammatory disorders, a family of diseases that is steadily expanding as additional members are described [1,34]. The duration of fever is a particularly useful discriminant since none of the other defined syndromes exhibit such prolonged episodes [35]. Other features particularly suggestive of TRAPS include myalgias, periorbital edema, and migratory rash [30]. (See "The autoinflammatory diseases: An overview".)

Familial Mediterranean fever — Familial Mediterranean fever (FMF) is a disorder characterized by episodic attacks of fever lasting one to three days and accompanied in most cases by abdominal pain, pleurisy, and arthralgias/arthritis secondary to serositis and synovitis. The diagnosis of FMF may be strongly suggested by patient ethnicity since this autoinflammatory disease is most commonly seen in certain ethnic groups including Sephardic Jews, Armenians, North Africans, and Turks and, to a lesser extent, Ashkenazi Jews, Greeks, and Italians [30]. (See "Clinical manifestations and diagnosis of familial Mediterranean fever".)

Hyperimmunoglobulin D syndrome — Hyperimmunoglobulin D syndrome (HIDS) is an autosomal recessive periodic fever syndrome most prevalent among patients of Dutch and French origin. Episodic attacks of fever lasting three to seven days are accompanied in most cases by chills, cervical lymphadenopathy, abdominal pain, vomiting, and/or diarrhea. Other symptoms include headache, arthralgias/arthritis, aphthous ulceration, a pleomorphic rash, and, occasionally, splenomegaly. Elevated levels of immunoglobulin D (IgD; >100 international units/mL) are often present, a finding that is not typical of TRAPS. Genetic testing is used to confirm the diagnosis of HIDS. (See "Hyperimmunoglobulin D syndrome: Clinical manifestations and diagnosis".)

PFAPA syndrome — Periodic fever with aphthous stomatitis, pharyngitis, and adenitis (PFAPA) is a syndrome for which the underlying etiology and pathogenesis are uncertain. Febrile episodes of abrupt onset last three to six days and are typically, although not invariably, accompanied by one or more of the following: pharyngitis (exudative or nonexudative), mild aphthous ulcerations, and lymphadenopathy. Recurrences of fever generally occur with nearly clockwork regularity, and laboratory markers of inflammation return to normal between episodes. There are no confirmatory laboratory tests for PFAPA, but the ability to "abort" an attack with a dose or two of systemic glucocorticoids is highly suggestive of the diagnosis. Many patients in series of "TRAPS" but lacking pathogenic or likely pathogenic variants in TNFRSF1A had a presentation consistent with PFAPA [9]. (See "Periodic fever with aphthous stomatitis, pharyngitis, and adenitis (PFAPA syndrome)".)

Cyclic neutropenia — Cyclic neutropenia may occur in both children and adults. It is characterized by periods of severe neutropenia that recur every 14 to 35 days, although nearly all patients exhibit a cycle period of 21 days. When neutropenic, patients are prone to malaise, fever, aphthous stomatitis, and, occasionally, serious infections. Cyclic neutropenia is suggested by documented neutropenia with an absolute neutrophil count below 500/microL on at least three to five consecutive days per cycle of each of three regularly spaced cycles. Neutropenia is not observed in TRAPS. Frequent monitoring of blood counts is necessary to observe the nadir. (See "Cyclic neutropenia".)

Interferonopathies — Interferonopathies are inflammatory diseases associated with excessive interferon signaling, typically of type I interferons [36]. Pathogenically, these disorders derive from variants that drive excessive interferon production or aberrantly amplify interferon signaling. The clinical spectrum and severity of these disorders are highly variable, but common features include persistent systemic inflammation, vasculopathic skin rashes ranging from chilblains to necrosis of acral tissues such as the nose and earlobes, pulmonary inflammation and fibrosis, lupus-like autoantibody production and resulting pathology, and, in some cases, brain inflammation with calcifications reminiscent of congenital viral infections (pseudo-TORCH syndrome) [36,37]. Fever can occur but is not typically a dominant feature, as it is in TRAPS. Assessment of peripheral blood gene expression data for an interferon signature, available as a research test, can facilitate the diagnosis of these rare conditions [38], but many related genes are also characterized in commercial panels testing genes associated with autoinflammation. (See "Autoinflammatory diseases mediated by interferon production and signaling (interferonopathies)".)

SCREENING ASYMPTOMATIC RELATIVES — Whether asymptomatic relatives of an affected individual should undergo genetic testing is uncertain. Amyloidosis may develop in the absence of febrile episodes, and some authors have suggested that genetic analysis and counseling be provided to asymptomatic family members [25]. However, the interpretation of genetic findings is complex, in particular for low-penetrance variants such as R92Q, P46L, and T61I. Accordingly, genetic screening of asymptomatic relatives is typically not recommended [39]. In families where the risk of amyloidosis appears particularly high, testing is an option after appropriate genetic counseling. If a variant is detected, these individuals should be followed carefully and should be treated if evidence of persistent, unexplained systemic inflammation or amyloidosis-related organ dysfunction is noted. (See 'Monitoring' below.)

MANAGEMENT

Goals of treatment — The goals of treatment of TRAPS are to control symptoms, prevent recurrent attacks, and reduce the risk of amyloidosis by suppressing systemic inflammation, particularly in patients bearing pathogenic or likely pathogenic cysteine variants [23]. (See 'Secondary (AA) amyloidosis' above.)

Amyloidosis in TRAPS and other periodic fever syndromes is closely associated with protracted unremitting inflammation [27]. Normalization of inflammatory markers is believed to result in the greatest likelihood of avoiding amyloidosis, although the extent to which achieving this target is required to avoid amyloidosis or whether therapy should be escalated to attain serologic remission in a patient who is already in clinical remission remain unknown. Patients bearing the low-penetrance variants R92Q and P46L generally exhibit less severe disease and a lower amyloidosis risk than those with cysteine variants and may tolerate less intensive treatment [28]. (See 'Genetics' above.)

Overview of treatment — On-demand treatment only is an option for the occasional patient with rare or mild flares and who maintains normal inflammatory markers between episodes. However, most patients have more frequent attacks and ongoing inflammation even between attacks. Higher doses, longer courses, and more frequent rounds of glucocorticoids all increase the risk of glucocorticoid toxicity. In addition, ongoing inflammation increases the risk of amyloidosis. Thus, most patients are treated with ongoing therapy, typically with cytokine blockade, rather than on-demand treatment alone. Oral glucocorticoids are tapered as tolerated based upon symptoms and inflammatory markers after prophylactic therapy is started. (See "Major adverse effects of systemic glucocorticoids" and 'Secondary (AA) amyloidosis' above.)

On-demand treatment of attacks

Mild attacks — For patients with mild flares (fever and mild discomfort easily tolerable by the patient), we suggest treatment with a nonsteroidal antiinflammatory drug (NSAID) alone (algorithm 1) [28,40]. Patients are typically treated with antiinflammatory doses of an NSAID, such as naproxen or ibuprofen, for three to five days. However, we suggest adding an oral glucocorticoid if symptoms increase. (See 'Typical attacks' below.)

Typical attacks — NSAIDs may help to control fever but are unlikely to terminate other clinical features of an attack [28,40]. Thus, for patients with an established diagnosis of TRAPS and a typical attack (eg, fever, myalgia, migratory rash, periorbital edema, and/or abdominal pain), we suggest initial treatment of attacks with an oral glucocorticoid (algorithm 1). This approach is based upon clinical experience in the absence of published data.

A typical agent is prednisone or prednisolone (initial dose of 1 mg/kg daily, maximum dose 60 mg/day, started at the onset of an attack followed by a gradual taper and discontinuation after 7 to 10 days). Fever and other symptoms should start to improve within the same day the glucocorticoid is started. Attacks may vary in severity. The glucocorticoid dose can be modified depending upon the degree of symptoms and the patient's own history of treatment response; for example, it may be necessary to increase prednisone or prednisolone to 1 mg/kg twice daily, or a patient may respond well to an initial dose of only 0.5 mg/kg/day.

There are a few case reports of successful on-demand treatment with anakinra, a recombinant interleukin (IL) 1 receptor antagonist, started within 24 hours of the onset of an attack and continued for approximately one week [41]. The benefit of this approach is that it can minimize or eliminate the need for glucocorticoids. However, it is not known whether therapy with anakinra only during attacks is sufficient to avert the risk of amyloidosis. Thus, where this option is selected, it remains essential to ensure that inflammatory markers normalize between clinical flares.

Prophylaxis

Frequent or poorly controlled symptoms and/or risk factors for amyloidosis

Initial prophylaxis – For patients with frequent attacks (arbitrarily defined and more than three to four attacks per year), inadequate response of attacks to oral glucocorticoids, persistent elevation of inflammatory markers between flares, and/or TNFRSF1A mutations classified as pathogenic or likely pathogenic, we suggest prophylactic therapy with canakinumab, a monoclonal antibody that neutralizes IL-1 beta (algorithm 1). The use of canakinumab is based upon limited clinical trial data and clinical experience. The initial dose of canakinumab is 2 mg/kg/dose (maximum dose 150 mg) administered subcutaneously every four weeks. The dose may be repeated after seven days and subsequent doses increased to 4 mg/kg/dose (maximum dose 300 mg) if the initial response is inadequate. (See 'Efficacy for symptom control' below and 'Efficacy for prevention of amyloidosis' below.)

Refractory disease – Treatment failure is defined as inadequate symptom control (frequency and/or severity of attacks), persistent elevation of inflammatory markers (C-reactive protein [CRP] and/or serum amyloid A), or evidence of amyloidosis. Anakinra is an alternative for patients who do not respond to or do not tolerate canakinumab. For patients in whom IL-1 blockade with both canakinumab and anakinra is ineffective or poorly tolerated, we suggest treatment with etanercept, a recombinant TNF receptor that inhibits TNF (algorithm 1). Use of etanercept is supported by small observational studies, case series, and clinical experience. There are limited observational data on use of tocilizumab, an IL-6 receptor antagonist, for patients with TRAPS. Thus, we reserve tocilizumab for patients in whom other treatment approaches have failed. (See 'Efficacy for symptom control' below and 'Efficacy for prevention of amyloidosis' below.)

Partial response to cytokine blockade – For patients with pathogenic or likely pathogenic variants who exhibit an incomplete response to cytokine blockade with canakinumab, anakinra, or etanercept, we suggest adding colchicine, 0.6 mg orally once to twice daily (algorithm 1). (See 'Efficacy for symptom control' below and 'Efficacy for prevention of amyloidosis' below.)

Efficacy for symptom control — In a phase II open-label study of 20 patients with active or recurrent chronic TRAPS treated with canakinumab prophylaxis (dosed at 2 mg/kg subcutaneously every four weeks, maximum dose 150 mg), 95 percent experienced excellent symptom control, typically within days of initiating therapy [42]. All patients flared off treatment, on average within 90 days of cessation of therapy, but responded with reinstitution of therapy. In a subsequent phase III trial of 46 patients with refractory TRAPS randomly assigned to canakinumab 150 mg (or 2 mg/kg if body weight ≤40 kg) subcutaneously or placebo every four weeks, a higher rate of complete resolution was seen with canakinumab than control (45 versus 6 percent, respectively) [19]. Resolution increased to 73 percent when those receiving a second dose of canakinumab for the initial flare were included. Among patients who had a complete initial response, 83 percent remained flare free when the dosing interval was increased to every eight weeks frequency compared with 27 percent in the placebo group. A long-term follow-up of 53 patients treated with canakinumab for TRAPS demonstrated continued efficacy, although two patients developed serious infections, including one in whom therapy had to be discontinued [43]. Canakinumab is approved by the US Food and Drug Administration (FDA) for the treatment of TRAPS [44]. Although canakinumab is associated with an increased risk of infections in patients with other risk factors (eg, older patients with comorbidities), no specific prevention strategies are recommended for patients receiving this treatment [45].

A potentially cost-effective alternative to canakinumab is anakinra, the recombinant IL-1 receptor antagonist. Unlike canakinumab, which has a half-life of approximately 24 days, anakinra is short acting, with a half-life of approximately four hours. Case reports and case series showed efficacy of anakinra 1.5 to 2 mg/kg/day (or 100 mg daily) in TRAPS, including as on-demand dosing in some patients [40,41,46-48].

In prospective case series and open-label studies, treatment with etanercept, a TNF inhibitor, was associated with reduced glucocorticoid requirement or a small decrease in disease activity scores, although the response was partial in some patients and absent in others, and inflammation was not abolished [3,49-51]. An observational study found that etanercept was helpful in 32 of 37 patients but induced complete remission in only 30 percent compared with 79 percent (26 of 33) for anakinra [40]. Etanercept is initiated at typical doses of 50 mg administered subcutaneously once weekly in adults and 0.8 mg/kg (up to 50 mg) weekly in children. Paradoxically, treatment with antibodies against TNF (infliximab and adalimumab) is associated with flares of disease and is generally avoided [28,52].

There are a few case reports of successful treatment of patients with TRAPS with tocilizumab [53-55].

Efficacy for prevention of amyloidosis — Case series, clinical experience, and extrapolation from other autoinflammatory disorders suggest that early institution of biologic therapy also lowers the risk of amyloidosis and kidney damage [27,29], although it is unclear how long treatment is needed to prevent this complication. Historically, anti-TNF therapy (etanercept) was employed for patients with frequent and/or severe recurrences and for those with TNFR1 gene variants associated with a high risk of amyloidosis. Patients with the V173D variant (interrupting metalloproteinase cleavage of TNFR1) may respond particularly briskly to this treatment [51]. However, the appreciation that IL-1 beta plays a key role in TRAPS has led to a preference for IL-1 blockade as the optimal strategy to secure long-term control and minimize amyloidosis risk [23,28].

Patients at low risk for amyloidosis and mild symptoms — For patients with TRAPS who wish to try prophylactic therapy but lack a pathogenic or likely pathogenic variant and who have symptoms that are unpleasant but tolerable, we suggest a trial of colchicine, at a dose of 0.6 mg orally once to twice daily, before initiating cytokine blockade (algorithm 1).

Several series have explored the utility of colchicine for TRAPS, largely in patients with R92Q and other low-penetrance variants [56,57]. In one retrospective series of 24 patients, colchicine therapy resulted in a complete response in 3 (13 percent), partial response in 14 (58 percent), and no response in 7 (29 percent) [56]. Stratifying by TNFRSF1A mutations, a response to colchicine was observed in only 2 of 19 patients (11 percent) bearing pathogenic or likely pathogenic variants but in 40 of 40 patients (100 percent) bearing either variants of uncertain significance or unclassified variants who also failed to meet Eurofever criteria for TRAPS [9]. No published information is available with respect to the impact of colchicine on amyloidosis risk.

Referral — Patients with persistent symptoms or those who develop amyloidosis despite biologic therapy should be referred to regional or national centers specializing in the investigation and care of this rare disease.

Monitoring — Patients with TRAPS should receive routine monitoring, including assessment of inflammatory markers (erythrocyte sedimentation rate [ESR] and CRP and, if available, serum amyloid A and S100 proteins) to assess extent of disease control and urinalysis to screen for proteinuria, which is the typical presenting feature of amyloidosis [28]. We perform such screening every 6 to 12 months, using quantitative measurement of spot urine protein and creatinine to screen for microalbuminuria, which is typically the earliest evidence of amyloidosis. Persistent elevation of inflammatory markers, in particular in the context of incipient amyloidosis, would be an indication for intensifying biologic therapy and/or referral to a center with specific TRAPS expertise.

Diagnosis of amyloidosis — Amyloidosis is usually identified on urinalysis screening, with the diagnosis confirmed by biopsy of kidney or intestine (see 'Monitoring' above). The duration between onset of TRAPS symptoms and diagnosis of amyloidosis has ranged from 3 to 71 years, with a median delay of 30 years [27,29]. However, amyloidosis can be diagnosed prior to TRAPS (see 'Secondary (AA) amyloidosis' above). The diagnosis of amyloidosis is discussed in greater detail separately. (See "Overview of amyloidosis", section on 'Diagnosis'.)

Treatment of amyloidosis — For patients with TRAPS who develop amyloidosis, we suggest treatment with IL-1 antagonists (canakinumab, anakinra) over anti-TNF therapy (etanercept). We treat to a level sufficient to fully normalize inflammatory markers. There are no randomized trial data. Some uncontrolled case series of patients with TRAPS have demonstrated reversal or slowing of progression of amyloidosis with treatment with etanercept [58-60], whereas others have shown good response to anakinra but only partial or transient response to etanercept [27,29]. There are no published data for canakinumab for AA amyloidosis in TRAPS, but use is supported by indirect evidence in treating other periodic fever syndromes such as familial Mediterranean fever (FMF) [61,62]. In addition, many patients prefer canakinumab over anakinra due to monthly rather than daily dosing. Treatment of AA amyloidosis is discussed in greater detail separately. (See "Treatment of AA (secondary) amyloidosis", section on 'Anticytokine therapy'.)

Pregnancy — Uncontrolled TRAPS has been associated with recurrent miscarriage, whereas successful pregnancy has been reported in TRAPS patients receiving IL-1 blockade [9]. While safety data regarding IL-1 blockade in pregnancy remain limited, requiring discussion of potential risks and benefits with each patient, continued IL-1 blockade during conception and pregnancy is recommended, typically with anakinra given its longer track record of use in pregnancy.

SUMMARY AND RECOMMENDATIONS

Genetics – Tumor necrosis factor (TNF) receptor-1 associated periodic syndrome (TRAPS) is a rare, autosomal dominant autoinflammatory syndrome resulting from pathogenic variants in the tumor necrosis factor receptor 1 (TNFR1) gene (TNF receptor superfamily member 1A [TNFRSF1A]). (See 'Genetics' above.)

Clinical manifestations – Attacks typically occur every five to six weeks. Clinical hallmarks include protracted febrile periods (at least six days, though typically longer), myalgias, periorbital edema, migratory rash, and abdominal pain. Elevated inflammatory markers (erythrocyte sedimentation rate [ESR] and C-reactive protein [CRP]) are noted during and between episodes. Persistent inflammation may result in secondary amyloidosis. (See 'Clinical manifestations' above.)

Diagnosis – The diagnosis of TRAPS is suggested by a history of recurrent fever and one or more of the other clinical features noted above, as well as absence of an underlying infection, autoimmune disease, or neoplastic disorder (table 1). The diagnosis is confirmed by genetic testing for common variants in the TNFR1 gene. (See 'Diagnosis' above.)

Differential diagnosis – The differential diagnosis includes all other causes of recurrent fevers, systemic lupus erythematosus (SLE), systemic juvenile idiopathic arthritis/adult-onset Still's disease, inflammatory bowel disease, vasculitis, and other autoinflammatory diseases. (See 'Differential diagnosis' above.)

Goals of treatment – The goals of treatment of TRAPS are to control symptoms, prevent recurrent attacks, and reduce the risk of amyloidosis by suppressing systemic inflammation, particularly in patients bearing pathogenic or likely pathogenic cysteine variants.

On-demand treatment of acute attacks:

Mild attacks – For patients with mild attacks (low-grade fever and mild discomfort easily tolerable by the patient), we suggest treatment with a nonsteroidal antiinflammatory drug (NSAID) alone (Grade 2C). If symptoms increase, an oral glucocorticoid can be added as is done for typical attacks. (See 'Mild attacks' above.)

Typical attacks – For patients with typical attacks (eg, fever, myalgia, migratory rash, periorbital edema, and/or abdominal pain), we suggest treatment with an oral glucocorticoid (Grade 2C). The usual regimen is prednisone or prednisolone 1 mg/kg daily, maximum dose 60 mg/day, started at the onset of an attack followed by a gradual taper and discontinuation after 7 to 10 days. An alternative is treatment with anakinra, a recombinant interleukin (IL) 1 receptor antagonist, beginning at 100 mg daily and escalating to 200 mg daily if needed. (See 'Typical attacks' above.)

Prophylactic therapy – On-demand treatment alone may be sufficient for the occasional patient with rare or mild flares and normal inflammatory markers between episodes. However, most patients with TRAPS have frequent attacks and/or ongoing inflammation even between attacks. Antiinflammatory agents (eg, colchicine) and/or cytokine blocking agents (eg, IL-1 antagonists [eg, canakinumab, anakinra] and TNF inhibitors [eg, etanercept]) are used in these patients to control the disease and reduce the risk of glucocorticoid toxicity. The choice of therapy depends on the patient's TNFRSF1A mutation status, severity and frequency of attacks, and whether there is evidence of amyloidosis. Our suggested approach is as follows (algorithm 1) (see 'Management' above):

Lower-risk patients – For patients with TRAPS who lack a pathogenic or likely pathogenic TNFRSF1A variant and who have symptoms that are unpleasant but tolerable, we suggest treatment with colchicine rather than on-demand treatment alone (Grade 2C). (See 'Patients at low risk for amyloidosis and mild symptoms' above.)

Higher-risk patients – This category includes patients with any of the following:

-Pathogenic or likely pathogenic TNFRSF1A variant

-Frequent attacks (more than three attacks per year)

-Inadequate response to oral glucocorticoids

-Persistent elevation of inflammatory markers between flares

-Evidence of AA amyloidosis

For patients with any of these findings, we suggest treatment with canakinumab rather than other agents or on-demand treatment alone (Grade 2C). For patients who do not respond to or do not tolerate canakinumab, anakinra is an acceptable alternative. For patients who do not respond to either IL-1 antagonist (canakinumab or anakinra), etanercept is a third-line option. (See 'Frequent or poorly controlled symptoms and/or risk factors for amyloidosis' above.)

Partial response – For patients with pathogenic or likely pathogenic TNFRSF1A variants who exhibit an incomplete response to cytokine blockade (eg, canakinumab, anakinra, or etanercept), we suggest adding colchicine (Grade 2C).

Patients with AA amyloidosis – For patients with TRAPS who develop amyloidosis, the mainstay of treatment is to achieve control of the disease with IL-1 antagonists (canakinumab, anakinra), as outlined in the previous bullets (algorithm 1). The target of treatment is to fully normalize inflammatory markers. (See 'Treatment of amyloidosis' above and "Treatment of AA (secondary) amyloidosis".)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges E Richard Stiehm, MD, who contributed as a Section Editor to earlier versions of this topic review.

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Topic 5580 Version 19.0

References

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