Persistent efficacy of anakinra in patients with tumor necrosis factor receptor-associated periodic syndrome.
ABSTRACT To evaluate the efficacy and safety of treatment with the interleukin-1 receptor antagonist anakinra in patients with tumor necrosis factor receptor-associated periodic syndrome (TRAPS) requiring high cumulative doses of steroids.
Four children (mean age 9.1 years [range 4-13 years]) and 1 adult (age 33 years) with TRAPS were enrolled in the study. The 3 children with cysteine mutations (C52Y, C55Y, C43R) had prolonged and frequent attacks of fever. One child with the R92Q mutation and the adult patient with the C43R mutation displayed a more chronic disease course, with fluctuating, nearly continuous symptoms and persistent elevation of acute-phase reactant levels (including serum amyloid A [SAA]). All patients were treated with anakinra (1.5 mg/kg/day).
All of the patients had a prompt response to anakinra, with disappearance of symptoms and normalization of acute-phase reactant levels, including SAA. In all pediatric patients, anakinra was withdrawn after 15 days of treatment. After a few days (mean 5.6 days [range 3-8]) a disease relapse occurred, which dramatically responded to reintroduction of anakinra. During the following period of observation (mean 11.4 months [range 4-20 months]), the patients did not experience episodes of fever or other disease-related clinical manifestations. Levels of acute-phase reactants remained in the normal range. No major adverse reactions or severe infections were observed.
Continuous treatment with anakinra effectively controlled both the clinical and laboratory manifestations in patients with TRAPS and prevented disease relapses.
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ABSTRACT: There is a thriving interest in the field of hereditary autoinflammatory disorders (HAID), a gamut of heterogeneous conditions deriving from an aberrant orchestration of innate immunity, unified by the common feature of seemingly unprovoked inflammation, which might be systemic or occur in localized niches of the organism. Recurrent fever and episodic inflammation in the joints, serosal membranes, skin, gut, and other organs are the common denominator of HAID. Mutations in the inflammasome-related genes have been associated with different HAID, showing the intimate link existing between interleukin-1 (IL-1)-structured inflammasome and their pathogenesis. Differential diagnosis of HAID can be challenging, as there are no universally accepted diagnostic protocols, and near half of patients may remain without any genetic abnormality identified. The use of IL-1-antagonists has been associated with beneficial effects in a large number of HAID associated with excessive IL-1 signalling, such as cryopyrin-associated periodic syndromes, familial Mediterranean fever, and deficiency of IL-1 receptor antagonist. This review will discuss about the key-clues of HAID which might guide for an early recognition and drive decisions for treatment.Autoimmunity Reviews 09/2014; · 7.10 Impact Factor
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ABSTRACT: The role of the potent proinflammatory cytokine IL-1 in disease could clinically be investigated with the development of the IL-1 blocking agent anakinra (Kineret®), a recombinant IL-1 receptor antagonist. It was first tested in patients with sepsis without much benefit but was later FDA approved for the treatment of patients with rheumatoid arthritis. More recently IL-1 blocking therapies are used successfully to treat a new group of immune-mediated inflammatory conditions, autoinflammatory diseases. These conditions include rare hereditary fever syndromes and pediatric and adult conditions of Still's disease. Recently the FDA approved two additional longer acting IL-1 blocking agents, for the treatment of cryopyrin-associated periodic syndromes (CAPS), an IL-1 dependent autoinflammatory syndrome. The study of autoinflammatory diseases revealed mechanisms of IL-1 mediated organ damage and provided concepts to a better understanding of the pathogenesis of more common diseases such as gout and Type 2 diabetes which show initial promising results with IL-1 blocking therapy.Annals of the New York Academy of Sciences 01/2009; 1182(1). · 4.31 Impact Factor
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ABSTRACT: The innate immune system is involved in the pathophysiology of systemic autoinflammatory diseases (SAIDs), an enlarging group of disorders caused by dysregulated production of proinflammatory cytokines, such as interleukin-1β and tumor necrosis factor-α, in which autoreactive T-lymphocytes and autoantibodies are indeed absent. A widely deranged innate immunity leads to overactivity of proinflammatory cytokines and subsequent multisite inflammatory symptoms depicting various conditions, such as hereditary periodic fevers, granulomatous disorders, and pyogenic diseases, collectively described in this review. Further research should enhance our understanding of the genetics behind SAIDs, unearth triggers of inflammatory attacks, and result in improvement for their diagnosis and treatment.Mediators of Inflammation 01/2014; 2014:948154. · 2.42 Impact Factor
ARTHRITIS & RHEUMATISM
Vol. 58, No. 5, May 2008, pp 1516–1520
© 2008, American College of Rheumatology
Persistent Efficacy of Anakinra in Patients With
Tumor Necrosis Factor Receptor–Associated Periodic Syndrome
M. Gattorno,1M. A. Pelagatti,1A. Meini,2L. Obici,3R. Barcellona,4S. Federici,1
A. Buoncompagni,1A. Plebani,2G. Merlini,3and A. Martini1
Objective. To evaluate the efficacy and safety of
treatment with the interleukin-1 receptor antagonist
anakinra in patients with tumor necrosis factor
receptor–associated periodic syndrome (TRAPS) re-
quiring high cumulative doses of steroids.
Methods. Four children (mean age 9.1 years
[range 4–13 years]) and 1 adult (age 33 years) with
TRAPS were enrolled in the study. The 3 children with
cysteine mutations (C52Y, C55Y, C43R) had prolonged
and frequent attacks of fever. One child with the R92Q
mutation and the adult patient with the C43R mutation
displayed a more chronic disease course, with fluctuat-
ing, nearly continuous symptoms and persistent eleva-
tion of acute-phase reactant levels (including serum
amyloid A [SAA]). All patients were treated with anak-
inra (1.5 mg/kg/day).
Results. All of the patients had a prompt response
to anakinra, with disappearance of symptoms and nor-
malization of acute-phase reactant levels, including
SAA. In all pediatric patients, anakinra was withdrawn
after 15 days of treatment. After a few days (mean 5.6
days [range 3–8]) a disease relapse occurred, which
dramatically responded to reintroduction of anakinra.
During the following period of observation (mean 11.4
months [range 4–20 months]), the patients did not
experience episodes of fever or other disease-related
clinical manifestations. Levels of acute-phase reactants
remained in the normal range. No major adverse reac-
tions or severe infections were observed.
Conclusion. Continuous treatment with anakinra
effectively controlled both the clinical and laboratory
manifestations in patients with TRAPS and prevented
Tumor necrosis factor receptor–associated peri-
odic syndrome (TRAPS), formerly known as familial
Hibernian fever, is a dominantly inherited disorder
caused by mutations in the gene for p55 TNF receptor
type I (TNFR1), which is encoded by the TNF super-
family receptor 1A gene (TNFRSF1A) (1,2). The disease
usually starts during childhood or adolescence and is
characterized by recurrent attacks of fever associated
with rashes, musculoskeletal and abdominal pain, and
periorbital edema. The duration of the attacks is vari-
able, ranging from a few days to several weeks. Some
patients have a fluctuating and subchronic disease
course, which is characterized by flares of abdominal
pain, arthralgia/myalgia, and ocular manifestations, with
or without fever, as well as by a persistent elevation of
the levels of acute-phase reactants, including serum
amyloid A (SAA). Renal AA amyloidosis represents the
most serious long-term complication of TRAPS, with a
prevalence ranging from 14% to 25% (3).
Episodes of fever are responsive to cortico-
steroids. However, escalating doses of steroids and re-
peated courses of treatment are sometimes needed,
especially in patients with frequent relapses or nearly
continuous symptoms. The use of immunosuppressive
drugs has been reported to be ineffective at reducing the
frequency and intensity of the episodes of inflammation
and/or preventing the development of amyloidosis in
TRAPS patients (3). The observation that the molecular
defect of p55 TNFR is associated with impaired shed-
Supported in part by grants from Telethon Italia and by the
Fondazione C. Golgi, Brescia, Italy.
1M. Gattorno, MD, M. A. Pelagatti, MD, S. Federici, MD, A.
Buoncompagni, MD, A. Martini, MD: Istituto Giannina Gaslini, and
University of Genoa, Genoa, Italy;2A. Meini, MD, A. Plebani, MD,
PhD: Spedali Civili, and University of Brescia, Brescia, Italy;3L. Obici,
MD, G. Merlini, MD: IRCCS Policlinico San Matteo, Pavia, Italy;4R.
Barcellona, MD: Azienda Ospedaliera Ospedali Riuniti di Sciacca,
Dr. Obici has received fees for lecturing (less than $10,000)
from Ortho Biotech.
Address correspondence and reprint requests to M. Gattorno,
MD, UO Pediatria II, Istituto Giannina Gaslini, Largo Gaslini 5,
Genoa 16145, Italy. E-mail: firstname.lastname@example.org.
Submitted for publication October 13, 2007; accepted in
revised form February 11, 2008.
ding of the receptor from the cell membrane led to the
proposal that anti-TNF treatment should be used in this
condition (2). Some initial anecdotal evidence supported
the efficacy of etanercept in the prevention of disease
flares (3,4) and in the treatment of long-term renal
complications (5). However, it has subsequently been
shown that anti-TNF therapy is ineffective in some
patients, but in others, it is unable to completely control
the inflammation (6,7).
An excellent short-term response to treatment
with recombinant human interleukin-1 (IL-1) receptor
antagonist (anakinra) in a patient with TRAPS has
recently been reported (6), suggesting that IL-1 block-
ade may represent a possible alternative strategy, as has
been observed in other monogenic autoinflammatory
diseases (8). In the present study, we examined the
efficacy and safety of anakinra treatment in 5 TRAPS
patients with a severe disease course.
PATIENTS AND METHODS
The main clinical and laboratory features of the
TRAPS patients at the time of enrollment are summarized in
Table 1. A total of 5 patients (4 children and 1 adult) were
studied. Patients 1–3 had a recurrent disease course, which was
characterized by frequent and severe attacks that limited their
normal daily activities, despite symptomatic treatment with
steroids and nonsteroidal antiinflammatory drugs (NSAIDs).
During the previous 6 months, these 3 patients experienced ?3
episodes of fever. The mean duration of each episode was 32
days in patient 1, 12.6 days in patient 2, and 15 days in patient
3. Patients 4 and 5 had a chronic course, with fluctuating,
nearly continuous symptoms and persistent elevation of the
levels of acute-phase reactants, including SAA, despite con-
tinuing treatment with steroids. None of the patients had renal
amyloidosis or proteinuria.
Based on our previous experience in treating patients
with other autoinflammatory diseases, anakinra was adminis-
tered subcutaneously at a dosage of 1.5 mg/kg/day (9). Patients
were treated for 15 days, and then the treatment was with-
drawn. In the event of a new disease flare, treatment was
restarted. Disease activity at the time of enrollment and during
the followup period was measured by evaluating the patient’s/
parents’ global assessment of disease activity (using a 0–10-cm
visual analog scale), the number and duration of episodes of
fever, the type of associated symptoms, and the serum levels of
C-reactive protein (CRP) and SAA. Laboratory evaluations
were performed on days 0, 3, 7, and 15, at the time of disease
relapse after treatment withdrawal, and monthly thereafter.
Patient 2 had been treated with etanercept when she
was 10 years old. After an initially complete control of episodes
of fever for 8 months, she experienced a gradual loss of efficacy
of anti-TNF treatment, with a progressively increased fre-
quency of attacks of fever. After 24 months of therapy,
etanercept was withdrawn.
Treatment with anakinra was started after informed
consent was obtained from the patients’ parents and, when
applicable, from the patients. The study was approved by the
Ethical Board of Giannina Gaslini Institute.
Patients 1–3, who had a recurrent disease course,
were treated 3–5 days after the beginning of a new
episode of fever. After the first 2 days of treatment, all 5
of the study patients experienced a prompt response to
anakinra, with disappearance of the fever and other
clinical manifestations of TRAPS (Figure 1). A dramatic
decrease in levels of acute-phase reactants was also
observed, with normalization after 15 days of treatment
(Figure 1). The 3 patients with a recurrent disease
course did not receive steroids before or during anakinra
treatment, whereas the 2 patients with a chronic disease
course were maintained on stable dosages of prednisone
In all pediatric patients (patients 1–4), anakinra
was withdrawn after 15 days of treatment. After a few
days (mean 5.6 days [range 3–8 days)], they experienced
a disease relapse. Reintroduction of anakinra resulted in
a prompt and dramatic response (Figure 1). After this
failed attempt to withdraw the anakinra, all of the
Clinical and laboratory features of the TRAPS patients at the time of enrollment*
mg of prednisone
* TRAPS ? tumor necrosis factor receptor–associated periodic syndrome; VAS ? visual analog scale (0–10 cm); CRP ? C-reactive protein (normal
?0.45 mg/dl); SAA ? serum amyloid A (normal ?6.8 mg/liter).
† Cumulative dose during the previous episode of fever.
EFFICACY OF ANAKINRA IN TRAPS PATIENTS1517
patients were given continuous treatment according to
the decision of the physician in charge and the willing-
ness of the patients and their parents to continue
During the following period of observation
(mean 11.4 months [range 4–20 months]), patients who
had previously had recurrent disease flares experienced
no episodes of fever or other disease-related clinical
manifestations, and therefore no longer required ste-
roid therapy. In addition, 1 of the 2 patients with a
chronic disease course (patient 4) was able to discon-
tinue steroid treatment. In patient 5, who also had
allergic asthma, the prednisone dosage was progres-
sively tapered and maintained at a dosage of 5 mg/day in
order to control his respiratory symptoms. Levels of
acute-phase reactants remained in the normal range.
The mean SAA at followup was 3.4 mg/dl (range 2.1–6.2
[normal ?6.8 mg/liter]).
Apart from variable skin reactions (pain, rash,
itching) at the site of the injections, which were observed
in all patients during the first weeks of treatment, no
serious adverse events were observed.
Episodes of fever associated with TRAPS are
usually characterized by a number of clinical manifesta-
tions (musculoskeletal and abdominal pain, rash, painful
periorbital edema) that greatly affect the patients’ daily
activities. In most patients, the symptomatic use of
NSAIDs and oral steroids is able to control the clinical
manifestations (3). However, some patients have a high
frequency of episodes of fever or develop a chronic,
fluctuating disease course that causes severe limitations
in normal social activities and requires prolonged ther-
apy with steroids. These patients are at major risk of
developing amyloidosis, the most severe long-term com-
plication of TRAPS (10).
Among the 32 individuals with TNFRSF1A mu-
tations diagnosed at our institution (11), only a few
displayed a particularly aggressive disease course that
required almost continuous treatment with steroids.
These included the 5 patients in the present study who
were treated with anakinra. All 5 of these patients
showed a dramatic response to the drug. Moreover,
continuous treatment with anakinra completely pre-
vented disease relapses during the followup period (11.4
months [range 4–20 months]).
TRAPS is caused by mutations in the TNFR1
gene. In their seminal article published in 1999, McDer-
mott and coworkers (2) showed that circulating mono-
nuclear cells from TRAPS patients displayed a defect in
the shedding of p55 TNFR. In fact, after cell activation,
the extracellular portion of both the p55 and the p75
isoforms of TNFRs may undergo metalloprotease-
dependent cleavage from the cell membrane. This pro-
cess produces a pool of soluble receptors that may
scavenge circulating TNF by competing with membrane-
bound receptors. This phenomenon represents an im-
portant strategy for regulating the effect of circulating
free TNF during acute inflammation. It was therefore
suggested that the defect in p55 TNFR shedding ob-
served in TRAPS patients could lead to inappropriate
TNF inhibition, and therefore uncontrolled inflamma-
tion (2). This raised the possibility that blocking the
excessive circulating TNF could potentially be the pri-
mary therapeutic strategy for TRAPS.
The first reports on the efficacy of etanercept in
TRAPS patients described an initially good response in
terms of a reduction in the frequency and intensity of
episodes (4). However, subsequent studies showed that
Figure 1. Response to anakinra in 4 pediatric patients and 1 adult
patient with tumor necrosis factor receptor–associated periodic syn-
drome (TRAPS). Changes in A, the acute-phase reactant C-reactive
protein (CRP) level and B, the patient’s/parents’ global assessment of
disease activity, as determined with the use of a 10-cm visual analog
scale (VAS), during the first days and months of anakinra treatment
and at followup in the 5 TRAPS patients are shown. After 15 days of
treatment, anakinra was withdrawn in the pediatric patients (patients
1–4). All 4 of these patients experienced a disease relapse during the
following days, but showed a prompt response to reintroduction of
anakinra (see Results for details). Followup assessment was performed
at 20 months in patient 1, at 12 months in patients 2 and 5, at 9 months
in patient 4, and at 4 months in patient 3.
1518 GATTORNO ET AL
treatment with anti-TNF agents was often unable to
totally eliminate the clinical and laboratory evidence of
inflammation (10). Moreover, as observed in our patient
with a C52Y mutation (patient 2), response to treatment
may wane with time (6), and resistant cases have been
reported (7). This raises the hypothesis that mechanisms
other than a lack of TNF buffering due to defective
TNFR1 shedding could play a relevant role in the
pathogenesis of the disease.
Indeed, mutations in the TNFRSF1A gene have
been associated with a number of other cell dysfunc-
tions. Circulating neutrophils and skin fibroblasts from
TRAPS patients display a defect in TNF-induced apo-
ptosis (11). Studies of cells transfected with the mutant
form of the TNFRI protein have shown a number of
relevant functional abnormalities, consisting of alter-
ations in trafficking and signaling of the mutated TNFRI
(12), with an accumulation of the protein in the endo-
plasmic reticulum (13). The intracellular consequences
of these functional abnormalities are still matter for
study. It is conceivable that they could lead from an
imbalance in the cellular response to a more pro-
nounced proinflammatory pathway (14).
The response to anakinra treatment in our
TRAPS patients is similar to the response observed in
patients with autoinflammatory conditions, such as
chronic infantile neurologic, cutaneous, articular
(CINCA) syndrome/neonatal-onset multisystem inflam-
matory disease (NOMID) or Muckle-Wells syndrome
(9), due to cryopyrin mutations. Cryopyrin is a key
protein of a multiprotein cytoplasmic complex called the
inflammasome. In the presence of a number of stimuli,
cryopyrin oligomerizes and binds to other intracellular
proteins. This association directly activates IL-1–
converting enzyme/caspase 1, which in turn, converts
proIL-1? into the mature, active 17-kd form.
Recently, it was shown that treatment with anak-
inra can be effective in other autoinflammatory condi-
tions, such as pyogenic sterile arthritis, pyoderma gan-
grenosum, and acne (PAPA) syndrome and familial
Mediterranean fever, in which the mutated proteins
have been shown to be functionally related to the
inflammasome (8), as well as in patients with systemic-
onset juvenile idiopathic arthritis (15).
These observations, together with the marked
response observed in our TRAPS patients, raise the
possibility that a dysregulation of IL-1? production and
secretion represents a possible final common pathway of
different monogenic or multifactorial inflammatory dis-
In conclusion, even if etanercept is still consid-
ered to be the first-line therapy for TRAPS, our study
provides evidence of the short-term and long-term effi-
cacy of IL-1 blockade. This suggests that anakinra could
be a valid alternative therapy for patients who require
prolonged treatment with steroids or who experience
frequent and long-lasting episodes of fever that lead to
severe limitations in their daily activities.
Dr. Gattorno had full access to all of the data in the study and
takes responsibility for the integrity of the data and the accuracy of the
Study design. Gattorno, Martini.
Acquisition of data. Gattorno, Pelagatti, Meini, Obici, Barcellona,
Federici, Buoncompagni, Martini.
Analysis and interpretation of data. Gattorno, Plebani, Merlini,
Manuscript preparation. Gattorno, Martini.
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