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Joint Bone Spine 74 (2007) 544e550

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Clinical-state-of-the-art

Auto inflammatory syndromes: Diagnosis and treatment

Katia Stankovic*, Gilles Grateau
Internal Medicine Department, Reference Center for Inflammatory Amyloidosis and Familial Mediterranean Fever, Tenon Teaching Hospital,
Assistance publique-hôpitaux de Paris, Paris 6 University, 4 rue de la Chine, 75970 Paris Cedex 20, France

Received 23 July 2007; accepted 25 July 2007

Available online 20 September 2007

Abstract

Hereditary recurrent fevers are rare genetic diseases characterized by apparently spontaneous attacks of inflammation. They include familial
Mediterranean fever (FMF); tumor necrosis factor (TNF) receptor periodic syndrome (TRAPS); hyperimmunoglobulinemia D syndrome
(HIDS); and hereditary periodic fevers related to mutations in the CIAS1 (cold induced autoinflammatory syndrome 1) gene, such as
MuckleeWells syndrome, familial cold urticaria, and CINCA/NOMID (chronic infantile neurological cutaneous and articular/neonatal-onset
multisystemic inflammatory disease). Musculoskeletal manifestations are common. They may occur as features of the acute inflammatory
attacks or persist for longer periods. Among them, the most common include arthritis of the large and medium-sized joints in FMF and CINCA,
arthralgia in HIDS, and myalgia or pseudo-fasciitis in TRAPS. The outcome is usually favorable, although joint destruction may develop in
CINCA or at the hip in FMF. The recurrent bouts of fever and accompanying clinical manifestations suggest the diagnosis, which can be con-
firmed by genetic testing. Among differential diagnoses, infection should be considered routinely. The treatment of the inflammatory attacks is
nonspecific. New pathophysiological insights have led to the development of promising maintenance treatments designed to reduce the number
and severity of the inflammatory attacks and to diminish the risk of secondary amyloidosis.
Ó 2007 Elsevier Masson SAS. All rights reserved.

Keywords: Hereditary recurrent fevers; Musculoskeletal manifestations

1. Introduction and articular/neonatal-onset multisystemic inflammatory dis-

Autoinflammatory syndromes are rare genetic diseases
characterized by recurrent attacks of inflammation. The pat-
tern of associated clinical manifestations, age at disease onset,
and course help to determine the diagnosis. The main auto-
inflammatory syndromes are hereditary recurrent fevers, which
include familial Mediterranean fever (FMF), also known as
periodic fever; tumor necrosis factor (TNF) receptor periodic
syndrome (TRAPS); hyperimmunoglobulinemia D syndrome
(HIDS); and hereditary periodic fevers related to mutations
in the CIAS1 (cold induced auto-inflammatory syndrome 1)
gene such as MuckleeWells syndrome, familial cold urticaria,
and CINCA/NOMID (chronic infantile neurological cutaneous
ease). Blau syndrome, Majeed syndrome, and Ghosal syndrome
have distinctive features and will not be discussed in this update.
Autoinflammatory syndromes differ from autoimmune diseases
in that no autoantibodies or autoreactive T cells are present.
Rheumatic manifestations are extremely common and highly
variable in their presentation and course. Any joint, including
the spine, may be involved. The pattern of musculoskeletal
involvement, concomitant manifestations, and course of the
clinical symptoms suggest the diagnosis, which can be con-
firmed by genetic testing. Once the exact diagnosis has been
established, a treatment strategy can be developed (Table 1).
2. Musculoskeletal manifestations in the
autoinflammatory syndromes

* Corresponding author. Tel.: þ33 1 56 01 70 80; Fax: þ33 1 56 01 70 82. Autoinflammatory syndromes are characterized by acute
E-mail address: katia.stankovic@tnn.aphp.fr (K. Stankovic). bouts of inflammation at various body sites, including the

1297-319X/$ - see front matter Ó 2007 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.jbspin.2007.07.005
Table 1
Features of the four main hereditary recurrent fevers
FMF HIDS TRAPS CINCA
Age at onset <20 years Early childhood Variable (mean, 10 years) Neonatal period/early childhood
Most characteristic extra-articular Pain in abdomen, chest, scrotum; Abdominal pain, cervical Periorbital edema, abdominal pain, Facial dysmorphia, ocular
signs erysipelas-like plaques lymphadenopathy, cellulitis-like lesions with pain in abnormalities, hearing loss, mental
hepatosplenomegaly, rash underlying muscles retardation, diffuse erythema
Predominant musculoskeletal Mono- or oligoarthritis Arthralgia Myalgia, arthralgia Oligoarthritis, muscle wasting
manifestations
Acute arthritis
Frequency 50e75% of cases Rare Rare 100% of cases

K. Stankovic, G. Grateau / Joint Bone Spine 74 (2007) 544e550

Joints involved (ranked by Knees, ankles, hips, shoulders, Large joints Knees, shoulders, elbows, hips, Knees (consistently involved), ankles,
frequency) elbows, wrists fingers, wrists, temporomandibular elbows, wrists, hips, small joints
joints
Duration of acute attacks 1e4 days 3e7 days Several weeks Variable
Chronic arthritis
Frequency 5% of cases e e 2/3 of cases
Joints involved Knees, hips (75% of cases), spine, e e Same as during acute attacks
sacroiliac joints, sternoclavicular
joints
Deformities Hips, knees e e
Radiological abnormalities Transient demineralization, None None Broad epiphyses, hypertrophy and
occasionally aseptic osteonecrosis of early ossification of the patella, moth-
femoral heads, degenerative disease eaten bone, physeal plate overgrowth
Myalgia Between attacks, three patterns: Common Fasciitis of the proximal limb Severe muscle wasting
extending to the extremity
espontaneous, no fever, moderate
pain; a few hours
eafter exercise, pain more severe,
a few hours to about 3 days
every severe, high-grade fever; a few
weeks; glucocorticoid therapy
Treatment
Acute attacks Analgesics, NSAIDs Analgesics, NSAIDs, limited Glucocorticoids Glucocorticoids
response to glucocorticoids
Chronic treatment Colchicine No proof that the new Etanercept IL-1 receptor inhibitor (anakinra)
immunomodulating drugs are
effective
Orthopedic treatment Hip: arthroplasty; knees: Chemical or surgical synovectomy
synovectomy
Inheritance Autosomal recessive Autosomal recessive Autosomal dominant Autosomal dominant
Gene MEFV MVK TNFRSF1A CIAS1
Protein Pyrin/Marenostrin Mevalonate kinase Type I TNF receptor Cryopyrin/ NLRP3

545
546 K. Stankovic, G. Grateau / Joint Bone Spine 74 (2007) 544e550
joints. A full recovery is the rule, although attack duration
varies across syndromes. However, chronicization may occur,
occasionally leading to functional impairment.
2.1. Acute musculoskeletal manifestations
About 50e75% of patients with FMF experience arthritis
during the inflammatory attacks [1]. Arthritis is the inaugural
symptom in 25% of cases. Onset of the joint manifestations is
before 10 years of age in 50% of cases. Monoarthritis is more
common than polyarthritis [2]. The large lower-limb joints
(knees, ankles, and hips) are the most common sites of in-
volvement, followed by the large upper-limb joints (shoul-
ders, elbows, and wrists); the metatarsophalangeal and
tarsal joints are less often affected [3]. Severe pain and a joint
effusion, which may be extremely large, develop in the ab-
sence of other evidence of inflammation. Complete resolution
within 1 week is the rule [4]. Radiographs show soft tissue
edema, occasionally with marked but transient deminerali-
zation [2,4].
Myalgia may occur between attacks of FMF. Spontaneous
episodes of moderate myalgia with no fever usually resolve
within a few hours. Physical activity may trigger episodes
of severe myalgia with low-grade fever lasting a few hours
to about 3 days [5]. Bouts of excruciating myalgia that pre-
cludes palpation of the muscles, accompanied with a high-
grade fever, may last for several weeks but usually respond
to glucocorticoid therapy [6]. In all these clinical patterns,
muscle enzyme levels are normal and the electromyogram
shows either normal findings or nonspecific myogenic in-
volvement [5]. Finally, some patients report pain in the lower
limbs that usually spreads from the feet to the thighs and in-
creases in severity over time. Erythema and edema may be
present. These episodes of pain are triggered by prolonged
standing or sitting, probably as a result of increased hydro-
static pressure [7].
Joint involvement is among the diagnostic criteria for
CINCA. The knee is nearly always affected. Other sites of in-
volvement, by decreasing order of frequency, include the
ankles, elbows, wrists, hips, and small joints [8,9]. Onset is
usually within the first year of life. Attacks of severe pain
and large effusions are followed by the development of chronic
joint effusions [8]. In less than one-third of cases, the joint
manifestations are less severe, with recurrent episodes of ar-
thritis that resolve within 2 weeks, normal radiographs, and
no residual abnormalities [8,10]. This pattern is also the most
common form of joint involvement in the other autoinflamma-
tory syndromes related to CIAS1 gene mutations.
About two-thirds of patients with TRAPS experience ar-
thralgia during the inflammatory attacks. The distribution is
mono- or oligoarticular. The most commonly affected joints
are the knees, shoulders, elbows, hips, fingers, wrists, and tem-
poromandibular joints. Arthritis is rare. Myalgia is extremely
common and may dominate the clinical picture [11]. Severe
myalgia with cutaneous inflammation may denote fasciitis,
which usually starts at the root of a limb and migrates toward
the extremity [11,12].
Attacks of HIDS may be associated with arthralgia of the
large joints. Arthritis develops occasionally, usually without
joint destruction [13].
Joint fluid obtained during arthritis attacks related to auto-
inflammatory syndromes shows inflammatory properties with
high neutrophil counts, no crystals, and negative microbiolog-
ical studies. Histological examination of the synovial tissue
demonstrates nonspecific inflammation characterized by ves-
sel dilation and infiltration by neutrophils and mononuclear
cells [4,8].
2.2. Chronic musculoskeletal manifestations
Chronicity is defined as persistence of the joint manifesta-
tions for longer than 1 month. Chronic musculoskeletal mani-
festations are seen chiefly in FMF and CINCA.
Chronic joint involvement occurs in 5% of patients with
FMF [14]. The knees and hips are involved in 75% of cases.
After an acute attack, the fever and local evidence of inflam-
mation resolve, but a large joint effusion persists. Joint pain
is severe and nearly continuous. These symptoms result in
functional impairment and rapid muscle wasting [2]. A full re-
covery within a few months is the usual outcome. Hip involve-
ment, however, has been reported to induce adverse outcomes
in 84% of cases. In particular, compression by the joint effu-
sion may cause aseptic osteonecrosis or degenerative disease
(joint space loss, osteophytes, and sclerosis) [2,4]. The sacro-
iliac joints are involved in only 6e12% of patients with FMF;
the course is usually chronic, and the involvement is bilateral
in half the cases [15]. Although other peripheral and spinal
manifestations of spondyloarthropathy may be present, there
are no syndesmophytes or bamboo spine [16]. One patient
had fusion of the spinal processes of C3 through C7 with cal-
cification of the anterior longitudinal ligament [17]. Tests are
negative for the HLA B27 antigen in most patients [18]. An
association between fibromyalgia and FMF has been reported
[19].
Articular involvement in CINCA starts in early childhood
and usually causes permanent joint deformities and muscle
wasting responsible for pain, flexion contractures, and func-
tional impairment. Radiographs show broad epiphyses, hyper-
trophy and early ossification of the patella, a moth-eaten
appearance of the bone tissue, periosteal reactions along the
tubular bones, and overgrowth of the physeal plates [8,9]. Joint
destruction simulating rheumatoid arthritis has been reported
[20].
2.3. Mean differential diagnoses and diagnostic strategy
In a patient with isolated febrile arthritis and evidence of
inflammation, joint aspiration is in order during the first attack
and whenever unusual symptoms occur, to look for septic ar-
thritis or crystal-induced arthritis [21]. Modern imaging tech-
niques constitute noninvasive tools for rapidly differentiating
septic arthritis from nonseptic arthritis. Studies are needed
to evaluate their diagnostic performance [22]. Recurrent epi-
sodes of oligoarticular involvement in a child suggest juvenile
 K. Stankovic, G. Grateau / Joint Bone Spine 74 (2007) 544e550
idiopathic arthritis; thus, the presenting features of Still’s dis-
ease consist of a fever, a nonurticarial skin rash, cervical
lymphadenopathy, and oligoarthritis [8]. In adults, early rheu-
matoid arthritis and other chronic inflammatory joint diseases
should be considered. Patients with hereditary recurrent fevers
have negative tests for antinuclear antibodies, rheumatoid fac-
tors, and anti-citrullinated peptide antibodies. The family his-
tory, ethnic origin, early onset within the first year of life or
neonatal period [23], concomitant manifestations, and course
suggest a hereditary recurrent fever. Genetic testing provides
the definitive diagnosis. In a patient with sacroiliitis or spinal
involvement, the absence of extra-articular manifestations
(e.g., ocular involvement, bowel disease, urethritis, and psori-
asis) militates against a spondyloarthropathy [17,19]. Further-
more, most patients with autoinflammatory syndromes are
negative for the HLA B27 antigen.
3. Main nonrheumatic manifestations of autoinflamma-
tory syndromes
3.1. Familial Mediterranean fever
Familial Mediterranean fever is the most common heredi-
tary recurrent fever. FMF selectively affects populations
from the Mediterranean rim including Sephardic Jews, Turks,
Arabs, and Armenians, as well as Ashkenazi Jews, Kurds,
Druzes, the Lebanese, Italians [24], and Greeks [25]. Symp-
toms start before 20 years of age in 90% of cases. The acute
attacks are characterized by a high-grade fever (usually
38.5  C to 39  C, occasionally 40  C) and inflammation of
one or more serous membranes (peritoneum in 90% of cases,
pleura, synovial membrane, tunica vaginalis, and pericar-
dium). Serositis may manifest as abdominal pain, chest pain,
and arthralgia or arthritis. The abdominal pain is often ex-
tremely severe and may lead to exploratory laparotomy if
the patient is not known to have FMF. Other symptoms include
changes in bowel habits (usually diarrhea), nausea, and vomit-
ing. Skin lesions are present in 7e40% of cases; they vary
widely, with the most common pattern being an erythematous
plaque simulating erysipelas. Laboratory tests show marked
inflammation with high neutrophil counts and elevated
acute-phase proteins. Each attack lasts a few hours to a few
days (3 days on average). Prodromal symptoms occur in about
half the patients; they may consist of either discomfort at the
site of the impending attack or neuropsychological manifesta-
tions such as irritability, lightheadedness, bulimia, or taste per-
version [26]. There are usually no symptoms between acute
attacks, although the joint involvement and myalgia may per-
sist for several weeks.
3.2. Autoinflammatory syndromes related to CIAS1 gene
mutations
Although these syndromes are all related to the same gene,
their features and severity vary. Familial cold urticaria is the
least severe CIAS1-related syndrome. Symptoms include mod-
erate-grade fever (38e38.5  C), urticaria, conjunctivitis, and
547
arthralgia. The distinctive characteristic is onset of the symp-
toms within a few hours after exposure to cold temperatures.
Attacks usually resolve within 24 h. Between attacks, patients
may experience symptoms such as headache, myalgia, asthe-
nia, and rash; these symptoms may occur nearly every day,
usually toward the end of the day or in the evening. Data es-
tablishing that an inflammatory response underlies familial
cold urticaria have prompted a change in the name of the syn-
drome, to familial cold-induced auto-inflammatory syndrome
(FCAS).
MuckleeWells syndrome manifests as attacks of urticaria
and fever, progressive sensorineural hearing loss starting in
childhood, and AA amyloidosis predominantly affecting the
kidneys. In addition to arthralgia and/or arthritis as described
above, features during the attacks include abdominal pain
and conjunctivitis. There is no specific link with cold expo-
sure. Attacks resolve spontaneously after 12 to 36 h and recur
at variable intervals, usually every few weeks [27]. Age at on-
set is variable.
CINCA or NOMID is characterized by neurological, cuta-
neous, and articular manifestations. Diffuse erythema without
pruritus may occur within a few days after birth. Chronic asep-
tic meningitis with neutrophils in the cerebrospinal fluid and
mental retardation develop progressively during childhood.
Inconsistent manifestations include ocular involvement (con-
junctivitis, uveitis, papillitis, and optic nerve atrophy poten-
tially responsible for blindness), bilateral progressive
sensorineural loss, facial dysmorphia, lymphadenopathy, and
hepatosplenomegaly.
3.3. Tumor necrosis factor (TNF) receptor periodic
syndrome (TRAPS)
TRAPS was first described in 1982 in a family of Irish and
Scottish descent and as a result was initially called ‘‘familial
Hibernian fever’’ [28]. Since then, cases have been identified
in other populations. Mean age at onset is 10 years. Each attack
lasts a few days to a few weeks (mean, 2 weeks). In addition to
a fever, the attacks are characterized in three-fourths of cases
by abdominal pain, which may suggest a surgical emergency.
The most common cutaneous manifestations are erythematous
cellulitis-like plaques with pain in the underlying muscles. This
pattern denotes fasciitis, which runs a chronic course over sev-
eral weeks. Urticaria is less common. Ocular manifestations
may include unilateral periorbital edema and, more rarely,
aseptic conjunctivitis, uveitis, and episcleritis [11].
3.4. Hyperimmunoglobulinemia D syndrome (HIDS)
The first cases of HIDS were identified in 1984 in a Dutch
family [29]. Most of the cases reported since then occurred in
families of Dutch or French descent, although patients have
also been identified in the UK, Germany, Italy, the Czech
Republic, Turkey, the Arab countries, Japan, and the US
[30]. Onset of the inflammatory attacks occurs within the first
year of life in the overwhelming majority of cases. Mean at-
tack duration is 7 days, and intervals between attacks usually
548 K. Stankovic, G. Grateau / Joint Bone Spine 74 (2007) 544e550
range from 4 to 8 weeks, being shorter in children and adoles-
cents then increasing with age [13]. High-grade fever
(>39  C) is accompanied in 60e75% of cases with chills,
abdominal pain, diarrhea, vomiting, headaches, arthralgia or
arthritis, cutaneous lesions (erythematous maculopapules, pe-
techiae, or purpura), and mucosal ulcerations. A distinctive
feature of HIDS compared to the other hereditary recurrent fe-
vers is the usual presence of lymphadenopathy; thus, cervical
lymphadenopathy is noted in 90% of cases and are usually
painful and firm. In addition, the liver and spleen are enlarged
in 50% of cases [13].
Serum levels of IgD are elevated (>100 IU/ml) during and
between the attacks in patients older than 3 years of age [31].
However, hyperimmunoglobulinemia D has also been reported
in patients with FMF or TRAPS [32]. IgA levels are elevated
in 80% of cases.
4. Genetic testing
FMF and HIDS are inherited on an autosomal recessive ba-
sis, whereas TRAPS and CIAS1-related diseases are dominant.
FMF is due to mutations in the MEFV gene (MEditerranean
FEver), which encodes pyrin (also known as marenostrin).
The first four mutations identified in 1997 account for 80%
of mutations causing FMF. Since then, over 70 mutations
have been identified. However, some of these mutations are
common in the ethnic groups affected with FMF, so that their
causal role in the syndrome remains to be confirmed. Further-
more, some patients with typical clinical manifestations have
heterozygous mutations or no detectable mutations, suggesting
a role for heretofore unidentified genes.
HIDS is due to mutations in the MK gene for mevalonate
kinase, which cause variable degrees of enzyme deficiency.
Over 60 mutations have been identified. HIDS is a mild
form of mevalonic aciduria, a pediatric disease responsible
for delayed growth, severe neurological disorders, dysmor-
phia, ocular abnormalities, and fever attacks. Mevalonic acidu-
ria, which is due to complete mevalonate kinase deficiency, is
often fatal in childhood.
The CIAS1 encodes a protein called cryopyrin, NALP3, PY-
PAF1, or more recently NLRP3. CIAS1 mutations are respon-
sible for familial cold urticaria, MuckleeWells syndrome, and
CINCA syndrome. About 20 mutations have been identified.
A given mutation may result in different phenotypes or in
overlap syndromes. CINCA is a severe disease that precludes
procreation, and the mutations therefore occur de novo. Muta-
tions may be identified in apparently healthy family members
of patients. These facts suggest incomplete penetrance and
a role for other genes and/or environmental factors [33]. Ge-
netic testing often fails to identify CIAS1 gene mutations in
patients with highly suggestive phenotypes; thus, up to 50%
of patients with CINCA have no identifiable CIAS1 mutations.
TRAPS is an autosomal dominant disease due to mutations
in the TNFSFR1A gene. To date, about 50 mutations have
been identified in nearly 200 patients who had clinical mani-
festations consistent with TRAPS [34]. A large number of
polymorphisms of the TNFSFR1A gene have been identified;
however, their relation to TRAPS remains to be demonstrated.
5. Amyloidosis
AA amyloidosis (i.e., inflammatory secondary amyloidosis)
is the most severe long-term complication of hereditary recur-
rent fevers. In contrast to immunoglobulin amyloidosis, trans-
thyretin amyloidosis, and b2-microglobulin amyloidosis
(dialysis-associated amyloidosis), AA amyloidosis usually
spares the skeletal system.
6. Treatment
The management of the acute attacks is nonspecific and
poorly standardized. Long-term treatments, in contrast, are
specifically designed to reduce the number and severity of
the inflammatory attacks, as well as to prevent the develop-
ment of amyloidosis.
6.1. Management of acute attacks
Several drug classes are generally used in combination, such
as analgesics and anti-inflammatory drugs, whose effectiveness
varies across patients, most notably in FMF. Glucocorticoid
therapy is usually effective in acute attacks of TRAPS and
CIAS1-related syndromes. Long-term glucocorticoid therapy
is responsible for many adverse effects, gradual loss of efficacy,
and dependency. In patients with CIAS1-related diseases, injec-
tion of the interleukin (IL)-1 receptor inhibitor anakinra (Kine-
retÒ) in a dosage of 1 mg/kg/day ensures attack resolution
within 24 h [35] and a return to normal of laboratory markers
for inflammation [36]. Attacks of HIDS fail to respond to glu-
cocorticoids, colchicine, and nonsteroidal anti-inflammatory
drugs.
6.2. Long-term treatment
In patients with FMF, colchicine is usually effective in pre-
venting the attacks and in preventing or halting the develop-
ment of amyloidosis. The effective dosage ranges across
patients from 0.5 to 2.5 mg/day. Children given colchicine
therapy had normal growth [37]. Colchicine has also been
found safe in pregnant women [38] and nursing mothers
[39]. When colchicine therapy fails to reduce the number of
attacks, adherence to the treatment should be evaluated, as
some patients take the medication only when they experience
attacks. If adherence is good, the dosage can be increased by
0.5-mg steps up to 2 or even 2.5 mg/day. A few cases of remis-
sion have been reported with interferon-a therapy [40], albeit
only at the cost of numerous adverse effects. Specific antago-
nists that target various proteins or receptors involved in the
inflammatory cascade (e.g., anakinra) may be effective in pa-
tients who are unresponsive to colchicine [41,42]. Studies are
ongoing to evaluate this possibility.
Sequential administration of the IL-1 receptor antagonist
anakinra (Kineret) showed promise for decreasing the frequency
 K. Stankovic, G. Grateau / Joint Bone Spine 74 (2007) 544e550
of attacks in patients with CIAS1 gene-related syndromes
[20,36]. However, the medication failed to halt the progression
of the auditory, ocular, and neurological disorders [33].
New insights into the pathophysiology of TRAPS have
prompted evaluation of etanercept as a long-term treatment.
Etanercept, obtained by fusing soluble type 2 TNF receptor
to an immunoglobulin, binds circulating TNF, which becomes
unavailable for binding to membrane receptors. In a study of 7
patients, etanercept was given subcutaneously in a dosage of
25 mg (0.4 mg/kg in children) twice a week for more than
6 months [43]. Decreases occurred in the number of attacks
and in glucocorticoid requirements. Further clinical trials are
needed to confirm these therapeutic effects and to evaluate
long-term safety.
Long-term treatments for HIDS have proved more disap-
pointing. Thalidomide and cyclosporin were not effective. Re-
sults with etanercept have been conflicting [44,45]. Whether
simvastatin is effective remains debated [46]. Anakinra was
found effective and safe in a single patient [47].
6.3. Orthopedic management
Aseptic osteonecrosis of the hip in patients with FMF can be
prevented by repeated joint aspiration. Total hip arthroplasty
can be offered to patients with disability due to advanced hip
disease. High rates of loosening and other postoperative com-
plications were noted in a study of 22 patients treated with to-
tal hip arthroplasty, indicating a need for careful selection of
the surgical procedure [48].
In patients who had massive, chronic, disabling knee effu-
sions, chemical or arthroscopic synovectomy improved knee
function and prevented recurrences [14,49]. However, the
risk/benefit ratio of these procedures should be evaluated on
a case-by-case basis.
7. Conclusion
Joint manifestations are extremely common in patients with
hereditary recurrent fevers. They range from arthralgia to
chronic destructive arthritis. Although the joint manifestations
are not specific, the concomitant presence of other symptoms,
family history, and disease course can suggest the diagnosis,
which can usually be confirmed by genetic testing. Differential
diagnoses that require specific treatment, such as septic arthri-
tis, should be scrupulously ruled out. The management of joint
symptoms during acute attacks is nonspecific. Promising med-
ications are available for decreasing the frequency of acute at-
tacks and for preventing amyloidosis, which is the most severe
chronic complication of the hereditary recurrent fevers.
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