INTRODUCTION — Many well-known disorders of immune excess result from 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." An overview of autoinflammatory diseases is presented separately. (See "The autoinflammatory diseases: An overview".)
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].
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 the subject of this topic review.
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/PATHOGENESIS — 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 tumor necrosis factor (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 individuals 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 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 specific genetic variant and clinical phenotype. However, the risk of secondary (inflammatory or amyloid A [AA]) amyloidosis is increased among patients with pathogenic variants affecting certain cysteine residues. (See 'Secondary (AA) amyloidosis' below.)
The pathogenesis of human TRAPS remains uncertain [9]. 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 [2,10]. Conversely, mutant receptor may bind TNF less efficiently, leading to impaired TNF-driven apoptosis [11,12]. Finally, mutant TNFR1 may misfold and/or traffic aberrantly within the cell [13-16]. 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 that is potentially 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 [16,17]. The resulting pivotal role of IL-1 beta is evident in the success of clinical antagonism of this cytokine [18].
CLINICAL MANIFESTATIONS — 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 88 to 100 percent of patients [3,4,8,19]. 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 [3,4,8,19]:
●Myalgias 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)
The rash may take a relatively characteristic form, with single or multiple erythematous patches (picture 1) that may spread distally down an extremity over time [20].
Presentation as recurrent pericarditis has also been reported [21].
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 [3,4,22-26]. This form of amyloidosis primarily involves the kidney. 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 [4,22]. 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 [3,4,22], 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 low (0 of 54 in one series) [4]. (See 'Management' below.)
LABORATORY FINDINGS — 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].
Patients with involvement of the kidney and other organs with secondary amyloidosis may have proteinuria, renal 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 [20]. 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) [27]. 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 [3,27]. 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 tumor necrosis factor receptor-1 (TNFR1) gene (TNFRSF1A). Testing is available commercially. While the R92Q variant 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 [6].
DIFFERENTIAL DIAGNOSIS — The differential diagnosis of recurrent fever is broad, including autoimmune diseases, other autoinflammatory diseases, and a number of 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 "Approach to the adult with fever of unknown origin".)
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. However, 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 [1,28]. The duration of fever is a particularly useful discriminant since none of the other defined syndromes exhibit such prolonged episodes [29]. Other features particularly suggestive of TRAPS include myalgias, periorbital edema, and migratory rash [27]. (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 [27]. (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 typically seen in 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. (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 recurs 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 type I interferon signaling [30]. Pathogenically, these disorders derive from variants that either 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) [30,31]. 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 [32], 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. However, 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 [23]. 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 [33]. 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 — The goals of treatment of TRAPS are to control symptoms, prevent recurrent attacks, and reduce the risk of amyloidosis associated with multiple cycles of fever and inflammation, particularly in patients bearing cysteine variants. Where possible, we aim to achieve normalization of inflammatory parameters as well as freedom from recurrent flares.
Amyloidosis in TRAPS and other periodic fever syndromes is closely associated with protracted unremitting inflammation [25]. Normalization of inflammatory markers is believed to result in the greatest likelihood of avoiding amyloidosis in these patients, 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 and may tolerate less intensive treatment [26].
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.
Treatment of typical attacks — Nonsteroidal antiinflammatory drugs (NSAIDs) may help to control fever, but glucocorticoids are almost always required to terminate other clinical features of an attack [26,34]. For patients with an established diagnosis of TRAPS and a typical attack, we suggest use of an oral glucocorticoid based upon clinical experience in the absence of published data. A typical agent is prednisone/prednisolone (initial dose of 1 mg/kg 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. For the patient with low-grade fever and mild discomfort, treatment with an NSAID alone is an option, although an oral glucocorticoid can be added if symptoms increase. The glucocorticoid dose can be modified depending upon the degree of symptoms.
Treatment of frequent and/or severe attacks — The goal of therapy in patients with frequent and/or severe attacks (based upon clinical judgement and patient/caregiver(s) input) despite treatment with oral glucocorticoids is prevention of recurrent symptoms and normalization of inflammatory markers. These patients are also at increased risk of developing amyloidosis [25]. Clinical experience and extrapolation from other autoinflammatory disorders suggest that early institution of biologic therapy also lowers the risk of amyloidosis, although it is unclear how long treatment is needed to prevent this complication. Historically, anti-tumor necrosis factor (TNF) therapy (etanercept) was employed for patients with frequent and/or severe recurrences and for those with TNF receptor-1 (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 [35]. However, the appreciation that interleukin (IL) 1 beta plays a key role in TRAPS has led to an increasing preference for IL-1 blockade [26].
Anti-interleukin 1 therapy — We suggest IL-1 antagonists as first-line biologic treatment for patients with frequent and/or severe recurrences, in particular for those with TNFR1 gene variants that are associated with a high risk of amyloidosis. Canakinumab is a monoclonal antibody that neutralizes IL-1 beta. The US Food and Drug Administration (FDA) has approved canakinumab for the treatment of TRAPS [36].
A phase-II clinical study treated 20 patients with active or recurrent chronic TRAPS with canakinumab (2 mg/kg subcutaneously every four weeks, maximum dose 150 mg). In this open-label study, 19 (95 percent) experienced excellent symptom control, typically within days of initiating therapy [37]. Patients were treated for four months, after which canakinumab was withdrawn. All patients flared off of treatment, but drug response was recaptured by reinstitution of therapy. Disease recurrence appeared on average approximately 90 days after the last canakinumab dose, suggesting the possibility that less frequent dosing could be effective. This was confirmed in the long-term extension phase, during which patients tolerated dosing every eight weeks, either at the original dose or, in some cases, at a higher 4 mg/kg dose. Gene expression studies supported the ability of canakinumab to reverse aberrant transcription associated with active disease, resulting in reduced expression of the gene encoding the defective TNF receptor itself [38].
This phase-II trial was followed by the phase-III CLUSTER randomized, controlled trial (Canakinumab Pivotal Umbrella Study in Three Hereditary Periodic Fevers) [18]. Forty-six patients with refractory TRAPS were randomly assigned to canakinumab 150 mg (or 2 mg/kg if body weight ≤40 kg) subcutaneously or placebo every four weeks. A second dose could be given if the baseline flare persisted between days 8 and 14 or had not resolved by day 15. A higher rate of complete resolution (resolution of baseline flare by day 15 and no additional flares by week 16) was seen with canakinumab than control (45 versus 6 percent, respectively). 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 and were randomly assigned to canakinumab or placebo given every eight weeks, 83 percent remained flare free from weeks 16 to 40 at this reduced dosing frequency compared with 27 percent of patients in the placebo group. The rate of serious infections in all patients on canakinumab in this trial was 7.4 per 100 person-years. However, infections were also observed during the placebo period, such that an associated increase infection risk could not be clearly established.
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 [34,39-42].
Whether intermittent therapy is sufficient to avert the risk of amyloidosis, in particular for patients who demonstrate persistent elevation of inflammatory markers between clinical flares, remains to be determined.
Anti-TNF therapy — Etanercept can be effective in some patients with TRAPS, although the response is partial in some patients and absent in others [3,35,43,44]. Thus, we reserve etanercept for patients in whom IL-1 blockade is ineffective or poorly tolerated.
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) has been associated with flares of disease and is generally avoided [26,45]. 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 [34].
IL-6 blockade — There are a few case reports of successful treatment of patients with TRAPS using the interleukin (IL) 6 receptor antagonist tocilizumab [46-48]. Given the limited data, we would reserve this option for unusual circumstances or failure of other treatment approaches.
Colchicine — Several series have explored the utility of colchicine for TRAPS, largely in patients with R92Q and other low-penetrance variants [49,50]. 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) [49]. No information is available with respect to the impact of colchicine on potential amyloidosis risk. We reserve colchicine (0.6 mg orally once to twice daily) for patients with mild symptoms and low predicted amyloidosis risk.
Monitoring — Patients with TRAPS should receive routine monitoring, including assessment of inflammatory markers (C-reactive protein [CRP] and, if available, serum amyloid A) to assess extent of disease control and urinalysis to screen for proteinuria, which is the typical presenting feature of amyloidosis [26]. We perform such screening at least 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 and treatment of amyloidosis — Amyloidosis is usually picked up on urinalysis screening, with the diagnosis confirmed by biopsy of kidney or intestine. 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 [25,51]. The diagnosis of amyloidosis is discussed in greater detail separately. (See 'Monitoring' above and "Overview of amyloidosis", section on 'Diagnosis'.)
Some uncontrolled case series of patients with TRAPS have demonstrated reversal or slowing of progression of amyloidosis with treatment with etanercept [52-54], whereas others have shown good response to anakinra but only partial or transient response to etanercept [25,51]. In the absence of trial data, we favor treatment with IL-1 antagonists over anti-TNF therapy in these patients and would treat to a level sufficient to fully normalize inflammatory markers. (See 'Anti-interleukin 1 therapy' above and 'Monitoring' above and "Overview of amyloidosis", section on 'Treatment'.)
SUMMARY AND RECOMMENDATIONS
●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). Penetrance is variable. (See 'Genetics/pathogenesis' above.)
●Clinical hallmarks include protracted febrile periods, myalgias, periorbital edema, and migratory rash. 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.)
●The diagnosis of TRAPS may be suspected on the basis of the history, physical examination, and absence of an underlying infection, autoimmune disease, or neoplastic disorder. The diagnosis is confirmed by genetic testing for common variants in the TNFR1 gene. (See 'Diagnosis' above.)
●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.)
●Preventing recurrent attacks and reducing the risk of developing amyloidosis are goals of therapy. (See 'Management' above.)
●For patients with an established diagnosis of TRAPS and a typical attack, we suggest use of an oral glucocorticoid (Grade 2C). Fever may respond to nonsteroidal antiinflammatory drugs (NSAIDs), but other clinical manifestations typically persist in the absence of glucocorticoid therapy. A typical agent is prednisone/prednisolone (initial dose of 1 mg/kg started at the onset of an attack followed by a gradual taper and discontinuation after 7 to 10 days). (See 'Treatment of typical attacks' above.)
●We suggest interleukin (IL) 1 antagonists as first-line biologic treatment for patients with frequent and/or severe recurrences, in particular for those with TNFR1 gene variants that have been associated with a high risk of amyloidosis (Grade 2C). Clinical experience and extrapolation from other autoinflammatory disorders suggest that early institution of biologic therapy lowers the risk of amyloidosis. In particular, we favor canakinumab because it has shown efficacy in treating flares, although there are no trial data regarding prevention of amyloidosis. Etanercept, an anti-TNF agent, may be equally effective in some patients and is an alternative when IL-1 blockade is ineffective or poorly tolerated. (See 'Treatment of frequent and/or severe attacks' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges E Richard Stiehm, MD, who contributed as a Section Editor to an earlier version of this topic review.
