Exposición de casos en los que se trata la Fiebre Mediterránea Familiar con un antagonista de la interleucina-1

1. Interleukin-1 Targeting Drugs in Familial Mediterranean
Fever: A Case Series and a Review of the Literature
Ulrich Meinzer, MD, PhD,* Pierre Quartier, MD, PhD,†
Jean-François Alexandra, MD,‡ Véronique Hentgen, MD,§
Frédérique Retornaz, MD,¶ and Isabelle Koné-Paut, MD, PhD*
Objectives: Familial Mediterranean fever (FMF) is an autosomal-recessive autoinflammatory dis-order
common in Mediterranean populations. FMF is associated with mutations of the MEFV
gene, which encodes pyrin. Functional studies suggest that pyrin is implicated in the maturation
and secretion of IL-1. The IL-1 receptor antagonist or anti-IL1 monoclonal antibody may there-fore
represent a new approach to treat FMF. The aim of this report was to evaluate and discuss
treatment of FMF with interleukin-1 targeting drugs.
Methods: Electronic mailing lists of French pediatric and adult rheumatologist associations were
used to call for FMF patients treated with interleukin-1 antagonists. A search for published FMF
patients treated with interleukin-1 targeting drugs was performed by screening PubMed.
Results: Here, we report 7 cases of FMF patients treated with anakinra and/or canakinumab and
discuss the clinical situations that may indicate the use of IL-1 blocking agents in FMF. The use of
interleukin-1 targeting drugs was beneficial to all patients. The reasons for using interleukin-1 targeting
drugs in FMF patients were as follows: (1) incomplete control of disease activity despite colchicine
treatment; (2) high serum amyloid A levels despite colchicine treatment; (3) impossibility to use
colchicine treatment because of severe side effects; (4) FMF in association with vasculitis.
Conclusions: Interleukin-1 targeting drugs may be good candidates when looking for an alternative or
supplementary treatment to colchicine. These observations highlight the need for controlled trials to
further evaluate the safety and efficacy of interleukin-1 antagonists in FMF patients.
© 2011 Elsevier Inc. All rights reserved. Semin Arthritis Rheum 41:265-271
Keywords: familial Mediterranean fever, interleukin-1, anakinra, canakinumab, inflammasome
Familial Mediterranean fever (FMF) is an autosom-al-
recessive autoinflammatory disorder more com-monly
observed in Mediterranean populations.
FMF is characterized by lifelong recurrent, self-limiting
attacks of fever and systemic inflammation. Serositis pre-senting
as peritonitis is present in most patients. Other
disease presentations include pleurisies, arthritis, pericar-ditis,
skin lesions, painful scrotum swelling, and myalgia
(1,2). The attacks typically occur every few weeks to
months and last for 1 to 3 days. The most important
long-term complication is progressive systemic type AA
amyloidosis (1,2).
The Mediterranean fever gene (MEFV) located on
16p13 encodes for pyrin (3,4). The exact function of
pyrin and the pathophysiologic role of the mutations are
not completely understood. However, recent data suggest
that the major role of pyrin is the regulation of caspase-1
activation. The inflammatory phenotypes of FMF are in-duced
by IL-1 and NF-B, which are abnormally acti-vated
by FMF-associated mutations of pyrin (5). Conse-quently,
the blockade of either IL-1 signaling or NF-B
activation represents possible targets for the treatment of
FMF (6,7).
*Division of Paediatric Rheumatology and Division of Paediatrics, CEREMAI,
Hôpital de Bicêtre; University of Paris Sud, Le Kremlin Bicêtre Cedex, France.
†Department of Paediatrics Immunohaematology and Paediatric Rheumatology,
Hôpital Necker-Enfants Malades, Paris, France.
‡Department of Internal Medicine, Hôpital Bichat Claude-Bernard, Paris, France.
§Department of Paediatrics, CEREMAI, Hôpital A Mignot, Versailles, France.
¶Departments of Internal Medicine and Infectious Diseases, Hôpital Ambroise-Paré,
Marseille, France.
IKP received research and consulting fees for lecturing (10,000 Euros) from
Novartis Pharma.
Address reprint requests to Ulrich Meinzer, MD, PhD, Division of Paediatric
Rheumatology and Division of Paediatrics, CEREMAI, Hôpital de Bicêtre; Univer-sity
of Paris Sud, 94275 Le Kremlin Bicêtre Cedex, France. E-mail: ulrich.
meinzer@bct.aphp.fr.
BIOLOGIC AGENTS
0049-0172/11/$-see front matter © 2011 Elsevier Inc. All rights reserved. 265
doi:10.1016/j.semarthrit.2010.11.003

2. 266 Interleukin-1 targeting drugs in familial Mediterranean fever
An increasing number of interleukin-1 targeting drugs
are currently in various stages of development. Anakinra,
a recombinant, nonglycosylated homolog of the human
IL-1 receptor antagonist, competitively inhibits binding
of IL-1 and IL-1 to the IL-1 receptor. Other drugs
include longer acting molecules such as canakinumab, a
human IgG1 monoclonal antibody directed against IL-
1, and rilonacept, an IL-1 blocker that comprises the
extracellular domain of the human type 1 IL-1 receptor
coupled to a human IgG1 antibody. None of them are
licensed for use in FMF patients.
Here, we present 7 FMF patients who were treated
with anakinra and/or canacinumab. Based on these cases
and those published by others, we discuss the possible
indications of interleukin-1 targeting drugs in FMF pa-tients
and review the literature.
METHODS
Electronic mailing lists of French pediatric and adult
rheumatologists societies were used to call for the medical
history of FMF patients (confirmed by carriage of 2
MEFV-mutations) who had been treated with interleu-kin-
1 targeting drugs. Information about age, sex, disease
course, treatment before anti-IL-1 targeting drugs, rea-sons
for the use of anti-IL-1 targeting drugs, treatment
modalities, clinical effect, side effects, and duration of
follow-up were recorded. As the genetic analyses were
performed as routine diagnosis procedure, there was no
requirement for institutional review board approval.
They included the E148Q variant in exon 2 and exon 10
sequencing of the MEFV gene. When a single mutation
was identified in exon 2 or 10, exons 2, 3, and 5 were
also systematically sequenced as described elsewhere
(8). As both anakinra and canakinumab were given
off-label for use in FMF, patients received comprehen-sive
information and gave their consent before receiv-ing
these treatments.
To identify publications reporting FMF patients
treated with interleukin-1 targeting drugs, we searched
PubMed using the search term “FMF” alone or in com-bination
with 1 of the following terms: “anakinra,”
“interleukin-1,” “canakinumab,” “rilonacept.”
RESULTS
Seven patients (4 male, 3 female) from 5 different hospi-tals
were identified. The patients’ ages when starting IL-1
targeting drugs were 51, 45, 12, and 7 years (4 patients).
Disease duration before the use of interleukin-1 targeting
drugs was 3 to 6 years in children and approximately 20
years in adult patients. MEFV gene analyses showed ho-mozygote
M694V mutations in 6 patients and composite
I692de/V726A, E149Q mutations in 1 patient (case 4).
FMF manifested with fever and abdominal pain in all
patients, thoracic pain (case 1), myalgia (case 6). The
patients’ clinical features are summarized in Table 1.
They were all treated with colchicine (1-2 mg/d) and
treatment was continued under interleukin-1 targeting
drugs in all patients except case 1. Six patients were
treated with anakinra and 1 patient with canakinumab.
One patient initially treated with anakinra was later
switched to canakinumab. Treatment modalities are
shown in Table 1. The reasons for using interleukin-1
targeting drugs in FMF patients were as follows: frequent
and severe FMF episodes despite colchicine treatment (2
patients); high serum amyloid A (SAA) levels despite col-chicine
treatment (2 patients); impossibility to use
colchicine treatment because of colchicine-induced toxic
neuromyositis (1 patient); FMF associated severe He-noch-
Schonlein purpura (HSP) (1 patient); and an atyp-ical
FMF episode with severe myalgia and generalized
convulsions (1 patient). The use of interleukin-1 targeting
drugs was beneficial to all patients (complete remission in
6 patients, partial remission in 1 patient). Observed ad-verse
effects were injection site reactions (3 patients) and
moderate headache (1 patient).
PubMed screen identified 8 single case reports of
FMF patients (5 adults, 3 children) treated with inter-leukin-
1 targeting drugs (9-16) (Table 2). MEFV gene
analyses were recorded in 6 patients. Five patients car-ried
homozygote M694V mutations (9,11,12,14,16)
and 1 patient carried heterozygote E148Q mutations
(10). All patients were treated with subcutaneous anak-inra
injections. In 2 patients anakinra was initially ad-ministrated
every 48 hours and later increased to daily
injections. In 1 patient who underwent hemodialysis
because of end-stage renal failure, anakinra was given 3
times weekly after hemodialysis (12). In another pa-tient
anakinra was administrated only on demand,
promptly after the onset of FMF episodes (9). The
reasons for using Anakinra were as follows: recurrent
FMF episodes with or without amyloidosis (6 patients)
(9-13,16); FMF associated with Behçet’s disease (1 pa-tient)
(14); pneumonitis in a renal transplanted patient
(1 patient) (15). The response to anakinra treatment
was complete remission in 6 patients and partial remis-sion
in 2 patients (9,13). Local injection site reactions
were the only observed side effects.
DISCUSSION
Here, we report 7 FMF patients who were treated with
interleukin-1 targeting drugs. Additionally, in the litera-ture
8 single cases have been published (9-16). Consider-ing
all published cases, the reasons for using interleukin-1
targeting drugs in FMF patients can be divided into the
following categories: (1) incomplete control of FMF dis-ease
activity despite colchicine treatment; (2) high SAA
levels and/or renal complications despite colchicine treat-ment;
(3) impossibility to use colchicine for the treatment
of FMF because of severe side effects; (4) FMF in associ-ation
with vasculitis.

3. U. Meinzer et al. 267
Table 1 Summary of Cases Reported in This Study
Sex,
Age
Reasons for the Use of IL-1
Targeting Drugs Treatment Modalities Clinical Effect
Follow-Up
(mo)
1 F, 45 yr Frequent (weekly) and severe FMF
episodes after colchicine
withdrawal because of
colchicine induced
neuromyositis
Anakinra s.c. daily 100
mg/d
Rare moderate episodes
without fever
18
2 M,51
yr
Frequent and severe FMF episodes
despite colchicine treatment,
impairing the quality of live.
The intensity of FMF attacks
obliged him to stay at home for
5 days/mo, negatively
impacting professional and
private live
Anakinra s.c. daily 100
mg/d
Complete remission 13
Anakinra s.c. 100 mg/48 h Reappearance of
episodes
Anakinra s.c. daily 100
mg/d
Complete remission
3 F, 7 yr Frequent and severe FMF episodes
(3 to 4/mo) despite colchicine
impairing the quality of life
Canakinumab s.c. (2 mg/
kg)/8 wk
Complete remission 5
4 F, 7 yr Severe episodes lasting for 5 days
twice a month despite
colchicine. Constantly elevated
SAA levels, even during
symptom-free intervals (200 to
834 mg/L), no signs of renal
impairment
Anakinra s.c. at onset of
crises 1 mg/kg/d
No change 2
Anakinra s.c. daily 1 mg/
kg/d
Complete remission,
normal SAA
3
5 F, 7 yr Frequent and severe FMF episodes
(3 to 4/mo) despite colchicine
with elevated SAA levels
between attacks (350 mg/L),
family history of renal
amyloidosis
Anakinra s.c. daily 1 mg/
kg/d
Complete remission,
normal SAA
4
6 M,12
yr
An atypical FMF episode with
severe protracted myalgia (class
III analgetics) and generalized
convulsions. No clinical effect
after colchicine dose increase to
1.5 mg/d
Anakinra s.c. daily 1 mg/
kg/d, during 14 d
Rapid clinical remission 8
7 M, 7 yr FMF associated to severe Henoch-
Schonlein purpura (HSP).
Continuous enteral feeding had
to be replaced by parenteral
nutrition. Treatment with
corticoids (2 mg/kg/d) and
immunglobulines (2g/kg for 2d)
did not change the severity of
HSV during 4 wk of
hospitalization
Anakinra s.c. daily 100
mg/d
Rapid clinical remission 16
After 6 months without FMF- and
HSP-manifestations Anakinra
was decreased and
discontinued. Ten days after
discontinuation, HSP-symptoms
reappeared
Canakinumab s.c. (2 mg/
kg)/8 wk
Rapid clinical remission 4

4. 268 Interleukin-1 targeting drugs in familial Mediterranean fever
Incomplete Control of Disease
Activity Despite Colchicine Treatment
The daily application of colchicine is the standard therapy
for prophylaxis of FMF attacks and amyloid deposition in
FMF. The beneficial role of colchicine for FMF attacks is
well documented by open-labeled studies in adult and
pediatric patients as well as placebo-controlled trials in
adult patients (17). Long-term application of colchicine
leads to a complete remission in two thirds of the patients
and partial remission (defined by significant decrease of
attack frequency or remission of a single symptom) in
approximately one third of the patients with FMF (17).
However, a minority of approximately 5 to 10% of the
patients does not respond to colchicine treatment (17). In
the latter, frequent and severe FMF attacks may severely
compromise the quality of life and increase the risk for
secondary amyloidosis. For example, insufficient disease
control with respect to severity and frequency of episodes
was the reason for introducing anakinra in cases 2 and 3 of
this report, as well as for most of the published single
cases. Anakinra for the treatment of colchicine-resistant
FMF has also been reported to be efficacious and safe in 2
adult patients with hemodialysis and/or renal transplan-tation
(12,16). This indication may represent the most
common situation for considering treatment of FMF
with anti-IL-1 targeting drugs.
Table 2 Summary of Cases Reported in the Literature
Author,
Reference
Sex,
Age
Reasons for the Use of IL-1
Targeting Drugs Treatment Modalities Clinical Effect
Follow-Up
(mo)
Belkhir 2007 [11] F, 68 yr Recurrent episodes despite
colchicine, elevated SAA
levels, AA amyloidosis
Anakinra s.c. 100
mg/48 h
Partial remission 0.5
Anakinra s.c. 100
mg/d
Complete remission 5
Discontinuation Relapse 2
Anakinra s.c. 100
mg/d
Complete remission 1
Calligaris, 2008
[13]
F, 15 yr Severe episodes despite
colchicine
Anakinra s.c. 1 mg/
kg/d
Partial remission 3
Discontinuation Relapse 3
Anakinra s.c. 1 mg/
kg/d
Partial remission 15
Mitroulis, 2008
[9]
M, 34
yr
Recurrent episodes despite
colchicine
Anakinra s.c. 100
mg/d at onset of
crisis
Partial remission 6
Roldan, 2008
[10]
Child Recurrent episodes despite
colchicine, persisting
inflammation
Anakinra s.c. 1 mg/
kg/d
Complete remission 6
Moser, 2009 [12] M, 43
yr
Recurrent episodes in a
end-stage renal failure
(AA amyloidosis) patient
recurrent episodes after
kidney transplantation
Anakinra s.c. 100 mg
3/wk after
dialysis
Complete remission 7
Anakinra s.c. 100
mg/d
Complete remission 20
Alpay, 2010 [16] F, 52 yr Severe diarrhea, weight
loss, persisting
inflammation, in a renal
transplant patient
Anakinra s.c. 100
mg/48 h
Constitutional
symptoms and
inflammation
normalized
2
Anakinra s.c. 100
mg/d
Bilginer, 2010
[14]
F, child Severe FMF episodes and
active Behçet’s disease
despite colchicine, renal
amyloidosis, proteinuria
Anakinra s.c. 1 mg/
kg/d
Complete remission
of both diseases
at 18 mo
proteinuria
reappeared
18
Hennig, 2010
[15]
M, 35
yr
Pneumonia with opacities
in radiograph of chest
attributed to FMF in a
renal transplant patient
Anakinra s.c. 100
mg/d
Clinical remission,
lung opacities
disappeared
ND

5. U. Meinzer et al. 269
Impossibility to Use
Colchicine because of Adverse Effects
Treatment with colchicine is generally safe and well tol-erated.
Most adverse effects to colchicine such as diarrhea
or nausea are mild to moderate and generally respond to
dose adaptation (17). Risk factors for toxicity of colchi-cine
treatment, such as renal impairment and drug asso-ciation
(eg, cyclosporine and macrolids), have been
described (18). Recommendations for the use of colchi-cine
have been addressed by Kallinich and coworkers (17)
and are regularly followed in our country. However, in
some patients severe adverse effects occur despite regular
prophylactic dosage, good patient compliance, and ab-sence
of risk factors. In case 1, for example, the patient
developed colchicine-induced neuromyositis.
Other rare adverse effects of colchicine susceptible to
impose treatment discontinuation and requirement of al-ternative
therapeutic approaches include bone marrow
alterations and dermatologic reactions (17).
High Serum Amyloid A Levels and/or Renal
Complications Despite Colchicine Treatment
The most important long-term complication of FMF is
progressive systemic type AA amyloidosis (1,2). The
localization is predominantly renal leading to chronic
renal failure but amyloidosis may also occur in other
sites such as gut, heart, endocrine glands, the spleen,
and the liver. AA amyloid fibrils are processed from the
acute phase reactant SAA protein (19). The SAA pro-duction
is highly correlated to amyloid burden and
renal dysfunction (20) and may therefore be used to
evaluate the risk for systemic amyloidosis. In cases 4
and 5 the constantly high SAA levels, even during the
symptom-free periods, indicated a high risk for the
development of systemic AA amyloidosis, and case 5
had additionally a positive family history of amyloido-sis.
In both cases the treatment with anakinra normal-ized
the SAA levels. Similarly, anakinra treatment
decreased the SAA levels of an adult patient with end-stage
renal failure (12). Together these reports indicate
that anakinra may be beneficial for decreasing the risk
of systemic AA amyloidosis in FMF patients with high
risk.
FMF Complicated by
Association with Other Diseases
FMF may be associated with other diseases and some-times
it is difficult to distinguish atypical FMF symptoms
from the associated disease. Whether FMF association to
other diseases results from a common causal factor or a
common pathomechanism remains to be explored. How-ever,
the higher frequency of FMF associated MEFV
mutations in some of the associated diseases is an obser-vation
that supports this theory. Thus, it is appealing to
think that controlling FMF may also be beneficial for the
control of the associated disease and vice versa.
In case 6 the patient presented with severe, protracted
myalgia and generalized convulsions. FMF-associated
convulsions are a rare, atypical disease manifestation that
has been described previously (21). Myalgia is present in
approximately 20% of FMF patients and may be classified
in spontaneous myalgia, exercise-induced myalgia, and
protracted myalgia syndrome (PFMS), which differ in
severity of pain, height of fever, and duration of the epi-sode
(22). Unless treated, the PFMS usually lasts for
weeks. In this patient, intensifying the colchicine treat-ment
with anakinra injections helped to rapidly control
PFMS.
In contrast, the motivation for the use of anakinra in
case 1 was not driven by FMF-attributed clinical manifes-tations
but by severe manifestation of the associated HSP.
The incidence of HSP in FMF patients is significantly
higher than in the normal population (2). Furthermore,
the occurrence of FMF-associated MEFV mutations is
higher in HSP patients when compared with the general
population (2).
Disease associations of FMF and/or increased carriage
of MEFV mutations have also been reported for a number
of other diseases, eg, polyarteritis nodosa (2), rheumatic
heart disease (23), and Behçet’s diseases (2). Interestingly,
anakinra treatment in a girl with FMF associated with
Behçet’s disease reduced the clinical symptoms of both
diseases (14).
Efficacy and Treatment Modalities
of IL-1 Targeting Drugs in FMF Patients
As case reports are currently the only available source of
information for the evaluation of the efficacy of interleu-kin-
1 targeting drugs in FMF, no reliable conclusions can
be drawn. Treatment with anakinra (1 mg/kg in children
and 100 mg/d in adults) or canakinumab (usual doses
2 mg/kg/8 wk in children under 40 kg and 150 mg/8 wk
in adults) was beneficial to all of the cases published here
and by others, suggesting that interleukin-1 targeting
drugs may be a good option when looking for a treatment
additional to or alternative to colchicine. One should nev-ertheless
bear in mind that off-label treated patients tend
to be reported only when results are positive. Controlled
trials are now necessary to evaluate the tolerance and effi-cacy
of interleukin-1 targeting drugs in FMF patients.
The duration of the treatment depends on the clinical
indication. In some cases anakinra may be necessary only
for a limited time to manage a difficult clinical situation.
In case 6, for example, anakinra was used for 2 weeks to
treat an episode of FMF-associated PFMS. In most
patients, however, interleukin-1 targeting drugs were
used to control the frequency and/or severity of FMF
episodes. This can be done either by using a chronic treat-ment
to prevent attacks or by an acute treatment at the
onset of the attacks. In all patients reported here and most
published cases, anakinra was used as a chronic, daily
treatment. In 1 case, however, anakinra was used punctu-

6. 270 Interleukin-1 targeting drugs in familial Mediterranean fever
ally directly after at the onset of the first clinical signs of an
FMF episode (9). The authors report that anakinra re-duced
the severity of the crises during a follow-up of 6
months, suggesting that in patients with good compli-ance,
early treatment at the onset of the attacks may be
considered. In contrast, in case 4 anakinra had no effect
on the severity of FMF episodes when used at the onset of
crises, whereas daily injections induced complete clinical
remission, indicating that daily injections may be more
efficient than treatment of crises only.
Another question is whether colchicine treatment
should be continued or discontinued when introducing
interleukin-1 targeting drugs. In patients with toxic side
effects to normally dosed colchicine, the dose can be ei-ther
reduced or stopped. In case 1, for example, consider-ing
the development of severe neuromyositis, the physi-cians
decided to completely stop colchicine. In all patients
in whom interleukin-1 targeting drugs were introduced
because of insufficient control of the disease activity, col-chicine
treatment was continued. This approach seems to
be safer, given the empirical character of treatment with
IL-1 targeting drugs vs the well-documented beneficial
effect of colchicine, especially in terms of preventing renal
AA amyloidosis.
Safety of Anakinra in FMF and Other Diseases
No reliable data about safety of interleukin-1 targeting
drugs in FMF patients are currently available. In other
diseases, however, including adult rheumatoid arthritis
and juvenile idiopathic arthritis, anakinra has been shown
to be well-tolerated in adults and children (24,25). In the
published FMF cases, local pain and inflammatory signs
at the injection site were the only reported side effects of
anakinra and canacinumab. Even though they tend to be
mild and improve over time, they may cause problems for
compliance or complicate the agreement to injections in
pediatric patients (case 7).
The potential risk of infections is a general concern
when using biotherapies. Serious infection in rheumatoid
arthritis patients treated with anakinra was the subject of
a recent meta-analysis (26). The overall pooled Odds Ra-tio
for serious infections did not show a significantly in-creased
risk. However, the risk was increased for a high
dose of anakinra vs low dose, and high dose vs placebo
(Odds Ratios 9.63 (95% CI: 1.31-70.91) and 3.40
(95% CI: 1.11-10.46), respectively). When patients with
comorbidity factors were excluded, the results were not
statistically significant whatever dose groups. This analy-sis
indicates a potential risk of serious infections, espe-cially
in patients with comorbidities. The risk of infec-tions
may also be higher in very young children in whom
the immaturity of the immune response is less effective
against polysaccharide encapsulated bacteria (27). By
consequence, from a practical point of view, the existence
of comorbidity factors should be taken into consideration
for the benefit-risk evaluations before treatment. Vaccina-tion
against Streptococcus pneumoniae should be updated
and in very young children antibiotic prophylaxis during
treatment should be considered. Finally, cholesterol and
triglyceride levels and blood cell counts should be moni-tored.
New Interleukin-1 Inhibitors
In all of the published patients (9-16) and in cases 1, 2,
and 4-7 of this report anakinra was used to target inter-leukin-
1 signaling. A number of other IL-1 inhibitors are
currently in different stages of development, including
the long-acting molecules canakinumab and rilonacept.
Whether long-lasting drugs should be used as a first-line
treatment (case 3), or only after having confirmed the
clinical benefit of silencing the IL-1 pathway with short-acting
drugs, or when compliance problems are encoun-tered
(case 7) needs to be discussed. Long-acting mole-cules
are indeed appealing because of their convenience of
use and may resolve problems with patient compliance.
However, data on safety and tolerance of these drugs are
currently very limited and their long-lasting effect cannot
be interrupted even when adverse effects occur.
CONCLUSIONS
Colchicine treatment is safe and effective in the large ma-jority
of FMF patients. However, the published cases in-dicate
that in some, rare patients the availability of an
alternative treatment would be desirable. The data for the
use of interleukin-1 targeting drugs in FMF patients are
currently limited to uncontrolled off-label use. Alto-gether,
the published cases indicate that interleukin-1 tar-geting
drugs may be good candidates when looking for a
treatment alternative to or supplementary to colchicine.
These observations highlight the need for controlled trials
to further evaluate the safety and efficacy of interleukin-1
antagonists in FMF patients.
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