Familial mediterranean fever: a fascinating model of inherited autoinflammatory disorder

Familial mediterranean fever: a fascinating model ofinherited autoinflammatory disorderPiero Portincasa*, Giuseppe Scaccianoce† and Giuseppe Palasciano*

*Clinica Medica “A. Murri”, Department of Biomedical Sciences and Human Oncology, University of Bari Medical School,Bari, Italy, †Gastrointestinal Endoscopy, “Umberto I” Hospital, Altamura, Bari, Italy

ABSTRACT

Background Familial Mediterranean fever (FMF) is a rare inherited autosomal recessive autoinflammatorydisorder characterized by recurrent and self-limited episodes of fever and painful serositis, lasting 1–3 days.FMF occurs almost exclusively among ethnic groups of the Mediterranean basin, although cases have also beenfound in Japan and Korean populations. Diagnosis is based on clinical features, response to colchicine andgenetic analysis. Novel drugs are emerging, allowing better management of colchicine-resistant/colchicine-intolerant patients. This review aims to attract the attention of the readers on differential diagnosis andmanagement of patients with FMF.

Methods The current state-of-the-art on FMF is outlined, with respect to epidemiological, genetic, patho-physiological and therapeutic characteristics, based on critical analysis of solid scientific literature.

Results FMF is more frequent than it was thought before. The phenotypic expression of M694V is more severethan that of V726A. Patients with M694V/M694V homozygosity are exposed to a higher risk of developing renalamyloidosis, arthritis, dermatologic and oral lesions, higher fever and more frequent painful attacks. Life-longtherapy with colchicine (1�0–2�4 mg/day) is effective and safe to prevent recurrent attacks and renal amyloidosisand to reverse proteinuria. In nonresponder patients, alternative novel approaches include interleukin-1 receptorantagonist anakinra and the interleukin-1 decoy receptor rilonacept.

Conclusions The prognosis of FMF is normal if AA amyloidosis is prevented. Colchicine remains the first-linetherapy to treat pain and prevent amyloidosis. A follow-up should include clinical evaluation, therapeuticadjustments, measurement of serum amyloid A and proteinuria.

Keywords Amyloidosis, anakinra, colchicine, periodic fever, pyrin, serositis.

Eur J Clin Invest 2013; 43 (12): 1314–1327

Introduction

Familial Mediterranean fever (FMF) is a rare inherited autoso-

mal recessive autoinflammatory disorder. Clinically, FMF is

characterized by recurrent and self-limited attacks of fever and

peritonitis, pleuritis, arthritis or erysipelas-like skin disease

with a marked acute-phase response. Late complications of

untreated patients are due to renal amyloidosis [1–4].

FMF occurs almost exclusively among ethnic groups of the

Mediterranean basin with Armenian, Arab, Jewish, Turkish,

North Africans and Arabic descent. The prevalence of FMF is

estimated to be 1 per 250 to 1 per 1000 in non-Ashkenazi

(Sephardic) Jews [5], 1 per 73 000 in Ashkenazi Jews [6], 1 per

500 Armenians [7], 1 per 1000 Turkish and 1 per 2600 Arabic

people. The carrier frequency is estimated to be 1 in 3 Arme-

nians [8], 1 in 5–10 Sephardic Jews [9], 1 in 5 Ashkenazi Jews [9]

and Turks [10]. Due to advancement of gene testing and

worldwide travelling and immigration, FMF cases have been

reported in Italians [11]. A novel cluster of FMF patients living

in Altamura (Apulia Region) in southern Italy has been recently

identified [12–14]. FMF is also found in populations like

Greeks, Cubans, Belgians [15], in countries like Sweden [16],

Germany [17] and other unexpected locations, such as Japan

[18–20] and Korea [21]. The worldwide prevalence is estimated

at 100 000–150 000 patients [22]. FMF in adults appears to be

more frequent in males with a ratio of M/F of 1�5–2 : 1.

Historical landmarks for FMF include the early report in 1908

by Janeway and Mosenthal of a Jewish girl with episodic fever

and abdominal pain (as outlined in ref. [1]); other cases were

described later as ‘fever of unknown origin’ [23], while the first

1314 ª 2013 Stichting European Society for Clinical Investigation Journal Foundation. Published by John Wiley & Sons Ltd

DOI: 10.1111/eci.12170

REVIEW

description of symptom pattern was in 1945 by Siegal as

‘benign paroxysmal peritonitis’ [24–26], and as ‘Periodic Dis-

ease’ by Reimann in 1949 [27] and Cattan and Mamou in 1951–

52 [28,29]. The term ‘FMF’ was used in 1958 by Heller et al. [30],

the use of colchicine in patients with FMF was due to Gold-

finger in 1972 [31], the mapping of FMF to the short arm of

chromosome 16 completed in 1992 [32,33] and the cloning of

the mutated gene (MEFV) by the French FMF consortium and

the International FMF consortium in 1997 [34–37]. FMF has

been known with the eponym of ‘Siegal-Cattan-Mamou syn-

drome’, ‘Reimann’s periodic disease’ or ‘syndrome’.

The information in this article is based on a synthesis of both

basic and clinical studies identified through exhaustive Pub-

Med literature search. Articles on FMF published in peer-

reviewed journals and ranging from 1949 to 2013 were

included. The term ‘FMF’ was cross-matched with ‘pyrin’,

‘MEFV’ and ‘autoinflammatory syndrome’ and with the MeSH

headings ‘natural history,’ ‘management’, ‘therapy’ and ‘path-

ophysiology’. Most complete articles were critically reviewed

by the authors and presented in this article.

Genetics and pathophysiology of FMF

FMF is caused by mutations of FMF gene (MEFV, Mediterra-

nean Fever) composed of 10 exons on chromosome 16p13.3,

which encodes pyrin (also named Marenostrin ‘our sea’ by the

French Consortium in 1997 [34]), a 781-aminoacid protein with

a molecular weight of 86 000. MEFV is expressed particularly

in myeloid cells and upregulated during myeloid differentia-

tion [38,39], and its expression is stimulated by some inflam-

matory mediators (i.e. tumour necrosis factor, TNF and

interferon-c).Pyrin is prominently expressed in the cytoplasm of mature

monocytes and neutrophils and also in dendritic cells and

synovial fibroblasts, cells derived from the colon and prostate

cancer [40]. Pyrin is detected in spleen, lung and muscle,

probably as a result of leucocyte infiltration in these tissues. The

protein acts as intranuclear transcription regulator of inflam-

matory peptides and participates in the inflammatory process

which is mediated by neutrophils [39]. In general, pyrin par-

ticipates in the events linked to the innate immune system

which is involved in the primary defence again noxious agents

and external pathogens [41]. Within the so-called inflamma-

some complex, pyrin, together with other proteins, can trigger

the conversion of pro-interleukin (IL)-1b to IL-1b [41–44], and

plays a fundamental role in fever, inflammation and apoptosis

[45]. As pyrin is the inhibitor of the complement-derived

mediator of inflammation C5a, as a result, patients with FMF

lack inhibition of neutrophil chemotaxis due to unregulated

production of IL-1b. In conclusion, as pyrin regulates the

inflammatory response by blocking intracellular signal

pathways via nuclear factor kB (NF-jB) or caspase 1, the

absence of pyrin function due to mutated MEFV leads to the

oversecretion of inflammatory cytokines [46]. Mutation of dif-

ferent components of the inflammasome, moreover, is respon-

sible for other autoinflammatory diseases within the group of

cryopyrin-associated periodic syndromes.

It is now clear that acute attacks in FMF develop because of

neutrophil activation at the serosal surface, as supported by

several evidences. The active role of neutrophils in the FMF

inflammation is confirmed by their presence in the serosal fluid,

the fast effect of colchicine treatment in preventing the attacks,

the expression of pyrin in neutrophils and the poor involve-

ment of protease in a number of inflammatory steps (Table 1).

The MEFV gene hosts multiple mutations, mainly on exon 10

between amino acids 680 and 761. The first three mutations

detected in 1997 by both research groups [34,35] in MEFV have

been M680IGC (G?C transversion at nucleotide 2040 that

results in substitution of isoleucine for methionine), M694V

(A?G transition at nucleotide 2080 causing substitution of

valine for methionine) and V726A (T?C transition at nucleo-

tide 2177 which results in substitution of alanine for valine).

The M694V and V726A mutations are some 2500-year-old

mutations originating from Middle East common ancestors

[35]. Another mutation on exon 1 at amino acid 148 appears to

be a frequent known mutation. Phenotypic expression can be

different according to MEFV mutation. For example, serum

amyloid type AA (SAA) deposition represents a late compli-

cation of untreated FMF and puts some patients at risk of end-

Table 1 Evidences supporting the role of neutrophil-mediatedinflammatory response in FMF

Factor Evidence

Neutrophils Presence of neutrophils in serosal fluid during

acute attacks

Colchicine Beneficial effect on prevention of attacks

Inhibition of chemotaxis and phagocytosis by

neutrophils

Pyrin/

marenostrin

Expression in the nucleus and cytoplasm in

circulating neutrophils

Lack of physiological inhibition of neutrophil

activation, and effect of neutrophil

cytoskeleton [115]

Lack of controlled inflammation

C5a/IL-8

inhibitor(s)

Poor expression of protease(s) involved in

inhibition of complement (e.g. C5a), IL-8, and

neutrophil chemotaxis [116–119]

C5a, complement fragment C5a; IL-8, interleukin-8.

Adapted from Grattagliano et al. [130], with permission from Nature Pub-

lishing Group, 2013.

European Journal of Clinical Investigation Vol 43 1315

FAMILIAL MEDITERRANEAN FEVER

stage renal disease and death. Certain ethnic groups are more

frequently exposed to the risk of amyloidosis, especially those

with the M694V mutation and especially in the presence of

homozygosity for M694V [47–50]. Also, homozygous M694V/

M694V patients are phenotypically more exposed to arthritis,

dermatological lesions, higher fever and more frequent attacks

and splenomegaly [51, 52]. Further studies show that E148Q

mutation is associated with the mildest and least penetrant

form of FMF [53].

As the disease is rare in non-Mediterranean populations, this

might mislead physicians to misdiagnose FMF as inflammatory

bowel disease (IBD) [20]. Recent studies suggest an association

between MEFV and IBD [54], but MEFV mutations make no

important contribution to IBD susceptibility [55] although there

is one IBD locus on the same chromosome, in the pericentro-

meric region [5]. In one recent case report, the patient showed

colonic lesions mimicking Crohn’s disease [55].

Likely, other genes may be implicated in FMF phenotype,

because symptomatic ‘FMF’ patients exist in the absence of

identifiable mutations in MEFV [56], suggesting an inconsistent

phenotype–MEFV correlation in FMF. In this respect, the major

histocompatibility complex class I chain-related gene A (MICA)

has been tested for polymorphism in exon 5 and identified as a

modifier locus of FMF. In particular, the influence of M694V

homozygosity on the age of FMF onset was more severe if

patients also inherited the MICA-A9 allele, while the fre-

quency of attacks was greatly reduced in patients with MICA-

A4 allele [57]. The MICA-A5 allele was subsequently found to

be protective against the development of amyloidosis in

Turkish patients [58]. Some additional proteins might modify

FMF characteristics: Armenian patients were analysed for

SAA1 and SAA2 genes (encoding for serum amyloid proteins)

and APOE gene (encoding for serum apolipoprotein E). The

risk of renal amyloidosis was especially high in the presence

of SAA1 alpha/alpha genotype and M694V homozygosity,

and male patients [59]. Turkish patients had similar charac-

teristics [60].

Diagnosis

Clinical featuresFMF begins in childhood (90% of patients experience the first

attack before the age of 20 years [3]), with sudden periodic

febrile attacks and serositis which, in order of frequency,

include peritonitis, arthritis, pleuritis, erysipelatous rash which

usually resolve spontaneously over 6–96 h (Fig. 1a,b).

The frequency of attacks can be variable, and no clear trigger

event has been identified. Temperature may reach 38–40 °C and

can anticipate other symptoms, although some patients may

present with fever alone [1]. Other patients may experience a

Hours0 24 48 72 96

Bod

y te

mpe

ratu

re (°

C)

36

37

38

39

40

41

Abdominal pain, chest pain, arthralgias (serositis) Skin rashes (eresypelas-like)

inflammation

FEVER

Days in a year0 30 60 90 120 150 180 210 240 270 300 330 360

Bod

y te

mpe

ratu

re (°

C)

36

37

38

39

40

41

Day 2Day 1 Day 4Day 3Jan Feb Mar Apr May Jun Jul Aug Sep Oct Nov Dec

(a) (b)

Figure 1 An example of the temporal profile of fever in a symptomatic patient with FMF is shown, before diagnosis wasestablished and colchicine therapy could be initiated. (a) The febrile attacks in a year are reported as peaks according to days andmonths. The cut-off value of 37 °C is shown as dotted horizontal line. In the period separating each attack, the temperature has beenconventionally set at 36�5 °C. A total of 14 attacks have occurred in a year in this patient. The black arrow indicates the febrile attackdepicted in (b). (b) Behaviour of a single febrile attack in a patient with FMF, with respect to time (hours). The relation with theinflammatory status and symptoms is illustrated (black horizontal arrow).


P. PORTINCASA ET AL. www.ejci-online.com

prodromic syndrome heralding attacks, consisting of discom-

fort, physical, emotional, neuropsychological complaints [61].

The dominant manifestation of the disease is peritonitis with

more than 90% of patients affected [4]. During attacks, most of

the patients may exhibit an initially localized pain which rap-

idly acquires the clinical picture of an acute abdomen, more

than simple abdominal pain. Especially when FMF diagnosis

has not been established, the occurrence of rebound tenderness,

guarding, adynamic ileus, rigidity and fever may put patients

with FMF at risk of unnecessary abdominal surgery, because

peritoneal manifestations may mimic a number of other con-

ditions including cholecystitis, appendicitis, renal colicky pain.

Remarkably, patients are totally asymptomatic in between

attacks, a period which can last from 1 week to several months.

Visceral adhesions may develop, due to recurrent peritoneal

inflammation. A consequence might be later onset of small

bowel obstruction and, in the case of pelvic adhesions, reduced

fertility in females.

Pleural manifestations (chest pain with transient pleural effu-

sions due to unilateral pleuritis or a pain which referred because

of subdiaphragmatic peritonitis) may occur in one-third of

patients with FMF [1,4]. Pericarditis occurs in < 1% of patients

[62].

Synovial symptoms occur by arthritis, due to the involve-

ment of joints, especially knees, ankles, hip, elbow and wrists,

usually mono- or oligo-articular. Permanent damage of joints is

unusual, and arthritis may be the only FMF manifestation.

While Ashkenazi Jews and Armenians suffer less from syno-

vitis, North Africans may present with more severe synovitis

[3]. Arthritis usually is not associated with joint destruction,

although it can last for several weeks or months. Thus, defor-

mity and functional limitations are rare. Migratory polyarthritis

are rare and might mimic acute rheumatic fever.

It is frequent to encounter dermatologic manifestations in up

to 50% of patients with FMF, particularly erysipelas-like rashes

on the lower extremities. Lesions are generally unilateral, occur

below the knee, ranging from 15 to 50 cm2, and are often

associated with swelling and tenderness [63]. Although the

clinical picture can resemble the infectious cellulitis, no treat-

ment with antibiotics is advised and recovery is spontaneous.

Physical examination in patients with FMF is unremarkable

during the intercritical attacks, but show brief febrile episodes

occurring with peritonitis and painful arthritis, without major

joint swelling. In the typical form, paroxysms (usually without

premonitory symptoms) last 2–4 days with greater intensity in

the first 12 h. Constipation is typically occurring during the

attacks and can be followed by late diarrhoea.

Fibromyalgia with tender muscles has been reported in FMF.

Other clinical manifestations associated with FMF may include

episodes of pericarditis, pelvic inflammatory disease, inflam-

mation of the tunica vaginalis with painful scrotal swelling

mimicking testicular torsion and orchitis [64], Henoch-Sch€onlein

purpura, Behc�et disease and polyarteritis nodosa [65] and pro-

tracted abdominal febrile myalgia [66].

Laboratory findingsNo common biomarker or imaging study is specific for FMF.

Inflammatory mediators include erythrocyte sedimentation

rate, serum C-reactive protein level, SAA, beta-2-microglobulin,

fibrinogen and white blood cells. Synovial fluid leucocyte count

can be elevated during febrile attacks (up to 1 000 000/lL) andconsists mainly of neutrophils [3,67]. When renal amyloidosis

has developed, proteinuria may be present in between attacks.

ComplicationsDeposition of SAA (anticipated by increased levels of SAA pro-

tein especially during acute attacks) is responsible for renal

involvement, the most important complication of FMF [68].

Proteinuria (> 0�5 g of protein per 24 h) observed in between

attacks should suggest amyloidosis in patients with FMF [69].

The risk of amyloidosis AA is higher in Sephardic Jews (30%)

than in Ashkenazi Jews [70] and can be as high as 60% in Turks

with FMF [3]. The evolution towards the nephrotic syndrome

and death from renal failure is higher in untreated patients. End-

stage renal disease might require 2–13 years after appearance of

proteinuria [4], and the use of colchicine has dramatically

decreased the incidence of amyloidosis in FMF. Thus, amyloi-

dosis will remain a problem for patients with FMF when the

diagnosis is delayed, adherence to therapy is poor, or the drug is

not available, and clinicians should put much attention to this

important clinical problem [71]. Amyloidosis, however, might

also affect the gastrointestinal tract (malabsorption) and the

vascular system (hypertension in about 35% of patients with

amyloidosis, risk of renal vein thrombosis). Other sites at risk of

AA amyloidosis can be the heart, thyroid and testes. A genetic

background for amyloidosis in FMFmight be important, because

in the presence of M694V mutation, the phenotypic manifesta-

tions of amyloidosis and arthritis are more frequent [35,72]. By

contrast, if amyloidosis is absent, ‘protective’ beta and gamma

alleles of type 1 SAA protein are more often detected [72].

Although the ultimate diagnosis of amyloidosis is established by

bone marrow or rectal biopsy [73], clinical criteria (persistent

proteinuria in patients with FMF) are sufficient ‘per se’ and

suggest amyloidosis.

Additional complications seen in patients with FMF (espe-

cially untreated) included subclinical cardiac autonomic dys-

function, similar to dysautonomia described in a variety of

rheumatic disorders [74].

Clues to diagnosisDiagnosis of FMF is based on clinical features, response to

treatment with colchicine [75] (see below), and genetic analysis.



Patients with typical symptoms and MEFV gene mutation are

defined as Type I phenotype. Those patients who have devel-

oped amyloidosis but had no typical attacks are defined as

Type II phenotype [30]. The so-called Tel Hashomer (named

from the city in central Israel) criteria have been developed and

are based on both major and minor criteria listed in a short or

extensive form [75] (Table 2). The overall diagnostic perfor-

mance of the criteria is good in diagnosing FMF adult patients,

Table 2 Clinical criteria for the diagnosis of FMF

(a) Tel Hashomer criteria

Major criteria � Recurrent febrile episodes with serositis� Amyloidosis of AA type without predisposing disease� Favourable response to colchicine treatment

Minor criteria

Diagnosis: definitive (2 major or 1 major + 2 minor criteria), probable (1 major + 1 minor criterion).

� Recurrent febrile episodes� Erysipelas-like erythema� FMF in a first-degree relative

(b) Detailed criteria

Major criteria Typical attacks:

1 Peritonitis (generalized)2 Pleuritis (unilateral) or pericarditis3 Monoarthritis (hip, knee, ankle)4 Fever alone

Minor criteria 1–3. Incomplete attacks involving one or more of the following sites:

1 Abdomen2 Chest3 Joint

4 Exertional leg pain5 Favorable response to colchicine

Supportive criteria 1 Family history of FMF2 Appropriate ethnic origin3 Age of < 20 years at disease onset

4–7. Features of attacks:

4 Severe, requiring bed rest5 Spontaneous remission6 Symptom-free interval7 Transient inflammatory response, with one or more test result(s) for white blood

cell count, ESR, SAA, and/or fibrinogen8 Episodic proteinuria/hematuria9 Unproductive laporatomy or removal of white appendix

10 Consanguinity of parents

The requirements for the diagnosis of FMF are at least 1 major criterion, or at least 2 minor criteria, or ≥ 1 minor criterion plus ≥ 5 supportive criteria, or ≥ 1

minor criterion plus ≥ 4 of the 5 supportive criteria. Typical attacks are defined as recurrent (≥ 3 of the same type), febrile rectal temperature of 38 °C or higher

and short (lasting between 12 h and 3 days). Incomplete attacks are defined as painful and recurrent attacks that differ from typical attacks in one or two

features: (i) the temperature is normal or lower than 38 °C; (ii) the attacks are longer or shorter than specified (but not shorter than 6 h or longer than a week);

(iii) no signs of peritonitis are recorded during the abdominal attacks; (iv) the abdominal attacks are localized; and (v) the arthritis is in joints other than those

specified. Attacks are not counted if do not fit the definition of either typical or incomplete attacks. Adapted from Livneh et al. Criteria for the diagnosis of

familial mediterranean fever. Arthritis Rheum. 1997;40:1879–85 [75].

ESR, erythro sedimentation rate; SAA, serum amyloid A.



but the specificity might be low (55%) in children, as shown

previously in the Turkish paediatric population [76]. The

explanation might be that children might poorly describe

severity and location of pain and that other clinical features of

attack might be different from those included in Tel Hashomer

criteria. Based on such assumption, a new set of clinical criteria

with high sensitivity and specificity for FMF in childhood has

been proposed and will require validation in different popu-

lations and/or in geographical areas different from Turkey,

where FMF prevalence is lower [76]. Differential diagnoses of

FMF are reported in Table 3 [1] and include other autoinflam-

matory syndromes and surgical and systemic conditions which

may resemble the FMF attacks.

Genetic testingPolymerase chain reaction may be able to establish diagnosis,

although genetic studies might not be ready for diagnostic use

[36,37]. In the Israeli FMF population, the 3 most common

MEFV mutations are M694V, V726A (alanine for valine at

position 726) and E148Q (glutamine [Q] substitutes for glu-

tamic acid [E] at position 148), and they appear to be related

to clinical presentation and disease severity using the Tel

Hashomer severity score [77]. All three mutations have more

amyloidogenic capability [6]. So far, total current number of

sequence variants for MEFV is 271 as obtained at the Hered-

itary Autoinflammatory Disorders Registry (Infevers database

[78–81]; Fig. 2). The use of clinical criteria in establishing the

diagnosis of FMF is still essential [77], because some patients

might display two classical mutations, some patients display

only one mutation, whereas some other might not display

known mutations at all (percentage ranging from about 30%

to 45%, depending on location) [77,82,83]. Indeed, it appears

that most subjects with two mutations remain clinically silent

[84].

Therapy

Treatment for FMF is based on the prevention of the painful

attacks and the development of amyloidosis (Table 4). Prophy-

lactic therapy with colchicine represents the mainstay of treat-

ment since 1972,when StephenE.Goldfinger atHarvardMedical

School first described thedramatic symptomatic improvement in

five patients with FMF treated with colchicine [31]. Other ther-

apeutic – nonconventional – options have been investigated. IL-1

inhibition might be the treatment option for most patients with

colchicine-resistant or colchicine-intolerant FMF.

ColchicineColchicine was originally extracted from the plant Colchicum

autumnale (the ‘meadow saffron’), and it has been known since

the Egyptian times for its antirheumatic properties.

Continuous use of colchicine (Fig. 3), an antigout and antimi-

totic agent, which decreases leucocyte motility and phagocytosis

in inflammatory responses, is recommended to prevent fre-

quency of attacks and amyloidosis [31,85]. A key rolewas played

by the very encouraging results obtained by the early controlled

trials in 1974 [86–88] using colchicine 0�6–1�8 mg/day. The short

duration of such trials (1–3 months) prompted other investiga-

tors to study the long-term (15 years) effects of colchicine 1�0–3�0 mg/day in 45 patients with FMF in 1992. A good, partial

response to treatment was seen in 87% of the patients, in terms of

severity, duration and frequency of attacks [89].

Colchicine should be started as soon as the diagnosis is

established, and therapy should continue for life, according to

the most current guidelines based on caregivers from Germany,

Austria and Turkey [90]. Based on FDA notes on colchicine for

acute gout flares and FMF issued in 2009 (FDA MedWatch 2009

July 31), safety and efficacy data demonstrated that a substan-

tially lower dose of colchicine was as effective as the higher dose

traditionally used. Those patients receiving the lower dose

experienced significantly fewer adverse events compared with

the higher dose. The dose of colchicine in patients aged

> 12 years ranges from 1�0 to 2�4 mg/day in 1–2 oral daily doses.

On the long term, treatment with colchicine will arrest the pro-

gression of AA amyloidosis and reverse proteinuria when

present and irreversible glomerular damage is absent [91].

Colchicine, however, might not totally prevent febrile attacks

[75]. Of note, colchicine given after kidney transplant in patients

with FMF can prevent the recurrence of FMF in the kidney

(proteinuria) [92].

Doses of colchicine must be lower in the presence of severe

hepatic impairment or renal impairment. The dose may vary

because of drug interaction due to concomitant use of CYP3A4

inhibitors according to the degree of inhibition (moderate: e.g.

grapefruit juice, verapamil; potent inhibition: e.g. clarithromy-

cin, ketoconazole). Guidelines indicate that colchicine can be

continued also during conception, pregnancy and lactation.

Indeed, use of colchicine during pregnancy in the treatment for

FMF has not shown an increase in miscarriage, stillbirth or

teratogenic effects, although data might be limited. Consensus

guidelines have been developed for the use of chronic colchi-

cine in children with FMF [90]. Adverse effects of colchicine

include abdominal pain, nausea, vomiting, diarrhoea, haema-

tological toxicity and myotoxicity (in patients with renal

impairment) and might require reduced dosing. Overall, it is

estimated that 30–40% of patients with FMF are partially

responsive to colchicine [85,93], 5–10% are resistant to colchi-

cine [94], and another 5–10% are intolerant to colchicine, mainly

because of gastrointestinal adverse effects [95]. Noncompliance

should be carefully considered in colchicine-resistant patients,

and patient should be instructed that noncompliance, as well as

interruption of colchicine treatment, will be followed by new



febrile attacks in a short time. Diagnosis different from FMF

including other hereditary autoinflammatory diseases should

be also taken into account in patients nonresponders to

colchicine (e.g. hyperimmunoglobulin D syndrome and

TNF-associated periodic fever). Conditions accounting for col-

chicine unresponsiveness are poorly understood, so far. Either

decreased gastrointestinal absorption or decreased intraleuco-

cyte concentration might be potentially involved [96,97].

Table 3 Commonest differential diagnoses of FMF

Group Disease Reference

Autoinflammatory

syndromes

Cyclic neutropenia [120]

Periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis syndrome (PFAPA) [121]

Cryopyrin-associated periodic syndromes

� Muckle–Wells syndrome� Chronic infantile neurological cutaneous articular (CINCA)/neonatal onset

multisystem inflammatory disease (NOMID)� Familial cold autoinflammatory syndrome (FCAS)

[122]

Hyper-IgD syndrome (HIDS) [123]

TNF-alpha associated periodic fever syndrome (TRAPS) [124]

Blau syndrome [125]

Chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE) [126]

Syndromes associated with deficiency of IL-alpha receptor antagonists [127]

Pyogenic arthritis, pyoderma gangrenosum, and acne syndrome (PAPA) [128]

Behcet’s disease [129]

Surgical

emergencies

Pancreatitis

Cholecystitis

Appendicitis

Intussusception

Peptic ulcer disease

Miscellanea Systemic lupus erythematosus

Lyme arthritis

HIV infection

Crystal-induced arthritis (gout, pseudogout)

Still’s disease

Sclerosing cholangitis

Whipple’s disease

Inflammatory bowel diseases

Urticaria

Hereditary angioedema

Acute intermittent porphyria

This list includes both autoinflammatory syndromes which require the differential diagnosis with FMF, and other surgical and systemic conditions which could

resemble the FMF attacks.



Further studies are required to establish whether i.v. colchi-

cine (1 mg weekly) in addition to oral colchicine might improve

the clinical outcome in FMF patients with refractory disease to

oral colchicine alone [98].

It is an open issue whether intermittent therapy with col-

chicine is advisable in a subgroup of patients who can

anticipate the painful attacks by prodromic symptoms.

Although this approach might improve compliance and be

somehow effective, as shown in early reports [99], a concern

exists about the persistent low-grade inflammatory status in

FMF occurring also during the intercritical phases. The ideal

subgroup of patients with FMF might be represented by

those with clear prodromic symptoms who respond to

intermittent colchicine and who have low genetic risk of

developing amyloidosis. Systematic monitoring of proteinuria

and markers of inflammation, including SAA levels, is

advisable [100].

As colchicine is not useful to stop an established attack,

administration of nonsteroid anti-inflammatory drugs (NSA-

IDs) should be considered for the treatment of pain (e.g. i.m.

diclofenac) [1].

AnakinraAnakinra is an IL-1 receptor antagonist and its use has been

proposed for the first time in 2007 [101–103]. Despite case

reports and uncontrolled series involving more than 30 patients

with FMF have been described [44,102–111], direct evidences

for anakinra in FMF are still lacking. Its use by daily injection,

causing important pain, is a potential contraindication in

chronic diseases.

RilonaceptIn colchicine-resistant or colchicine-intolerant patients with

FMF, rilonacept, an IL-1 decoy receptor, has been tested in a

Figure 2 Infevers: an online database forautoinflammatory mutations. Copyright.Available at http://fmf.igh.cnrs.fr/ISSAID/infevers/ Accessed (15 Septempter 2013)[78–81].

Table 4 Current therapeutic approaches in symptomatic FMF patients

Drug Mechanism Notes Reference

Colchicine Antigout and antimitotic agent

Prevention and treatment of acute

painful attacks, and amyloidosis

Lifelong therapy [31, 90]

Anakinra IL-1 receptor antagonist

Daily injection required

Effective in one case, but lacking direct evidence [101]

Rilonacept IL-1 decoy receptor

Longer half-life

Once week administration

Randomized, double-blind, single-participant

alternating treatment study (6 males and 6 females)

Reduced frequency, not duration, of FMF attacks

[112]

Steroids are ineffective in preventing or treating attacks

IL-1, interleukin-1.



small randomized placebo-controlled trial [112]. Rilonacept is a

complex protein consisting of the extracellular domain of

humanized IL-1 type I receptor and the IL-1 receptor accessory

protein which are fused with the Fc portion of IgG1. The final

result is ‘trapping’ of IL-1. The longer half-life of rilonacept (6�3– 8�6 days) makes the administration suitable once a week. In

the reported trial, 12 participants with FMF resistant to or

intolerant of colchicine, mainly of Armenian, Arab and Ash-

kenazi ethnicity (M694V, M694I, E148Q, V726A, K695R, R329H,

A744S mutations), received rilonacept 2�2 mg/Kg (maximum

160 mg) given subcutaneously once weekly for 3 months. Ri-

lonacept significantly reduced the frequency of FMF attacks by

76% and was better (39%) than the 3-month course with pla-

cebo [112]. Quality of life also improved. Notably, rilonacept

did not decrease the duration of attacks. Further studies are

required to bring rilonacept to the level of evidence-based

therapy in FMF.

Prognosis, prevention and screening

Mortality due to nephrotic syndrome secondary to AA amy-

loidosis was frequent before the institution of colchicine ther-

apy in 1972 or can still be a worrisome evolution in

undiagnosed cases. It was estimated that about 60% of patients

older than 40 years developed amyloidosis [113]. In the absence

of AA amyloidosis, patients with FMF have a normal life

expectancy.

The course of FMF appears to be more severe in subjects with

Jewish descent (with more frequent M694V mutation also as

homozygous) compared with subjects with Arab descent

[48,114]. Some patients with prevalent peritoneal episodes

might be at risk of increased rate of appendectomy, due to

appendicitis-like clinical picture. About 30% of FMF females

are infertile, and foetal loss may occur in 20–30% of

pregnancies.

Because of the genetic features of FMF, no definitive pro-

gramme of prevention and screening is applicable. Historical,

geographical, ethical considerations and direct observation of

attacks are of key importance to establish the diagnosis (see

also Fig. 1). Genetic analysis has some limitations: it is not

always available and can be expensive, and genetic laborato-

ries might restrict the analyses to the most frequent mutations

(M694V, V680I, V726A, E148Q and V694I); therefore, missing

the most rare mutations. Molecular testing should be taken

into account when the diagnosis is highly probable, but col-

chicine treatment should be started when patients are symp-

tomatic [113]. If genetic testing is negative, the diagnosis is

highly likely if symptoms are responsive to treatment and

return after stopping treatment. In this case, one should think

OO

O

O

O

HNHN

O

(S)-N-(1,2,3,10-tetramethoxy-9-oxo-5,6,7,9-tetrahydrobenzo[a]heptalen-7-yl)acetamide

Chemical Formula: C22H25NO6Molecular Weight: 399·4

(a)

(b)

(c)

Figure 3 Colchicine. (a) structure,systematic name, chemical formula andmolecular weight. (b) Tridimentionalstructure, and (c) ‘space filling’ modeldisplay. In (b, c), the (c) atoms are depictedin grey, the six O atoms are depicted in red,and the N atom is depicted in light blue.



that genetic mutations not identified yet are responsible for

symptoms.

Follow-up

Follow-up should be offered to patients with FMF who need to

accomplish therapeutic compliance to avoid poor quality of life

and risk of amyloidosis. This aspect is particularly relevant in

teenagers who are typically a noncompliant group and need

long-term daily therapy to prevent chronic complications. A

urinalysis is needed at every visit and is important in patients at

risk of developing amyloidosis. Compliance should be assessed

whether proteinuria is present, and other causes of proteinuria

includingheavysports activity shouldbe ruledout. If proteinuria

is confirmed, the daily dose of colchicine need to be increased.

Conclusions

Despite FMF is deemed as a rare inherited condition worldwide,

it achieves remarkably high prevalence in some populations

with Mediterranean ancestors. Historical and geographical fac-

tors have facilitated the diffusion of FMF in many areas in the

world, and this aspect should be taken into account when

approaching the final diagnosis. The combined features of FMF

make this inherited disorder a fascinating model in which com-

plex genetic, phenotypic, pathophysiological and therapeutic

aspects interact. The simple, effective and safe lifelong therapy

with colchicine, even at an early age, is going to stay as the most

effective way to prevent the painful clinical manifestations and

the late most serious complication of renal amyloidosis.

Acknowledgements

We thank for their support Antonio Stacca, Major of the Town

of Altamura, Paolo Calveri (President of the Italian Association

of Periodic Fever, AIFP), Vitangelo Dattoli (General Director of

the Academic Hospital Policlinico of Bari, Italy), Nicoletta Resta

and Alessandro Stella (Section of Human Genetics, University

of Bari). We are indebted to Paola De Benedictis, Rosa De

Venuto, Michele Persichella and Valentina Ruggiero for their

skilful technical assistance, and to Ignazio Grattagliano and

Leonilde Bonfrate for kindly revising the text. Part of the work

was supported by Fondazione Cassa di Risparmio di Puglia

(Research Grant 2012).

Address

Clinica Medica “A. Murri”, Department of Biomedical Sciences

and Human Oncology, University of Bari Medical School, Bari,

Italy (P. Portincasa, G. Palasciano); Gastrointestinal Endoscopy,

“Umberto I” Hospital, Altamura, Bari, Italy (G. Scaccianoce).

Correspondence to: Prof. Piero Portincasa, MD, PhD, Clinica

Medica “A. Murri”, Department of Biomedical Sciences and

Human Oncology, University of Bari Medical School – Policli-

nico, 70124 Bari, Italy. Tel.: +39-80-5478-227; fax +39-80-5478-232;

e-mail: [email protected]

Received 10 March 2013; accepted 28 August 2013

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Familial mediterranean fever: a fascinating model of inherited autoinflammatory disorder

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