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Keywords:

  • Amyloidosis;
  • anakinra;
  • colchicine;
  • periodic fever;
  • pyrin;
  • serositis

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Genetics and pathophysiology of FMF
  5. Diagnosis
  6. Therapy
  7. Prognosis, prevention and screening
  8. Follow-up
  9. Conclusions
  10. Acknowledgements
  11. Address
  12. References

Background

Familial Mediterranean fever (FMF) is a rare inherited autosomal recessive autoinflammatory disorder 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 been found in Japan and Korean populations. Diagnosis is based on clinical features, response to colchicine and genetic 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 and management of patients with FMF.

Methods

The current state-of-the-art on FMF is outlined, with respect to epidemiological, genetic, pathophysiological 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 severe than that of V726A. Patients with M694V/M694V homozygosity are exposed to a higher risk of developing renal amyloidosis, arthritis, dermatologic and oral lesions, higher fever and more frequent painful attacks. Life-long therapy with colchicine (1·0–2·4 mg/day) is effective and safe to prevent recurrent attacks and renal amyloidosis and to reverse proteinuria. In nonresponder patients, alternative novel approaches include interleukin-1 receptor antagonist anakinra and the interleukin-1 decoy receptor rilonacept.

Conclusions

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


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Genetics and pathophysiology of FMF
  5. Diagnosis
  6. Therapy
  7. Prognosis, prevention and screening
  8. Follow-up
  9. Conclusions
  10. Acknowledgements
  11. Address
  12. References

Familial Mediterranean fever (FMF) is a rare inherited autosomal 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 Armenians [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 description of symptom pattern was in 1945 by Siegal as ‘benign paroxysmal peritonitis’ [24-26], and as ‘Periodic Disease’ 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 Goldfinger 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 syndrome’, ‘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 PubMed 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 ‘pathophysiology’. Most complete articles were critically reviewed by the authors and presented in this article.

Genetics and pathophysiology of FMF

  1. Top of page
  2. Abstract
  3. Introduction
  4. Genetics and pathophysiology of FMF
  5. Diagnosis
  6. Therapy
  7. Prognosis, prevention and screening
  8. Follow-up
  9. Conclusions
  10. Acknowledgements
  11. Address
  12. References

FMF is caused by mutations of FMF gene (MEFV, Mediterranean 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 differentiation [38, 39], and its expression is stimulated by some inflammatory mediators (i.e. tumour necrosis factor, TNF and interferon-γ).

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 inflammatory peptides and participates in the inflammatory process which is mediated by neutrophils [39]. In general, pyrin participates 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 inflammasome complex, pyrin, together with other proteins, can trigger the conversion of pro-interleukin (IL)-1β to IL-1β [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-1β. In conclusion, as pyrin regulates the inflammatory response by blocking intracellular signal pathways via nuclear factor kB (NF-κB) or caspase 1, the absence of pyrin function due to mutated MEFV leads to the oversecretion of inflammatory cytokines [46]. Mutation of different components of the inflammasome, moreover, is responsible 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 involvement of protease in a number of inflammatory steps (Table 1).

Table 1. Evidences supporting the role of neutrophil-mediated inflammatory response in FMF
FactorEvidence
  1. C5a, complement fragment C5a; IL-8, interleukin-8.

  2. Adapted from Grattagliano et al. [130], with permission from Nature Publishing Group, 2013.

NeutrophilsPresence of neutrophils in serosal fluid during acute attacks
ColchicineBeneficial effect on prevention of attacks
Inhibition of chemotaxis and phagocytosis by neutrophils
Pyrin/marenostrinExpression 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]

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[RIGHTWARDS ARROW]C transversion at nucleotide 2040 that results in substitution of isoleucine for methionine), M694V (A[RIGHTWARDS ARROW]G transition at nucleotide 2080 causing substitution of valine for methionine) and V726A (T[RIGHTWARDS ARROW]C transition at nucleotide 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 complication of untreated FMF and puts some patients at risk of end-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 pericentromeric 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 frequency 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 characteristics [60].

Diagnosis

  1. Top of page
  2. Abstract
  3. Introduction
  4. Genetics and pathophysiology of FMF
  5. Diagnosis
  6. Therapy
  7. Prognosis, prevention and screening
  8. Follow-up
  9. Conclusions
  10. Acknowledgements
  11. Address
  12. References

Clinical features

FMF 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).

image

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

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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 prodromic syndrome heralding attacks, consisting of discomfort, 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 rapidly 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 conditions 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 effusions 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 involvement 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 synovitis, 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, deformity 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 treatment 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, inflammation of the tunica vaginalis with painful scrotal swelling mimicking testicular torsion and orchitis [64], Henoch-Schönlein purpura, Behçet disease and polyarteritis nodosa [65] and protracted abdominal febrile myalgia [66].

Laboratory findings

No 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/μL) and consists mainly of neutrophils [3, 67]. When renal amyloidosis has developed, proteinuria may be present in between attacks.

Complications

Deposition of SAA (anticipated by increased levels of SAA protein 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, amyloidosis 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 FMF might be important, because in the presence of M694V mutation, the phenotypic manifestations 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 (especially untreated) included subclinical cardiac autonomic dysfunction, similar to dysautonomia described in a variety of rheumatic disorders [74].

Clues to diagnosis

Diagnosis 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 developed 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 performance of the criteria is good in diagnosing FMF adult patients, 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 populations 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 autoinflammatory syndromes and surgical and systemic conditions which may resemble the FMF attacks.

Table 2. Clinical criteria for the diagnosis of FMF
  1. 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].

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

(a) Tel Hashomer criteria
Major criteria
  • Recurrent febrile episodes with serositis
  • Amyloidosis of AA type without predisposing disease
  • Favourable response to colchicine treatment
Minor criteriaDiagnosis: 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 pericarditis
  3. Monoarthritis (hip, knee, ankle)
  4. Fever alone
Minor criteria

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

  1. Abdomen
  2. Chest
  3. Joint
  4. Exertional leg pain
  5. Favorable response to colchicine
Supportive criteria
  1. Family history of FMF
  2. Appropriate ethnic origin
  3. Age of < 20 years at disease onset

4–7. Features of attacks:

  1. Severe, requiring bed rest
  2. Spontaneous remission
  3. Symptom-free interval
  4. Transient inflammatory response, with one or more test result(s) for white blood cell count, ESR, SAA, and/or fibrinogen
  5. Episodic proteinuria/hematuria
  6. Unproductive laporatomy or removal of white appendix
  7. Consanguinity of parents
Table 3. Commonest differential diagnoses of FMF
GroupDiseaseReference
  1. 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.

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 

Genetic testing

Polymerase 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 glutamic 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 Hereditary 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].

image

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

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Therapy

  1. Top of page
  2. Abstract
  3. Introduction
  4. Genetics and pathophysiology of FMF
  5. Diagnosis
  6. Therapy
  7. Prognosis, prevention and screening
  8. Follow-up
  9. Conclusions
  10. Acknowledgements
  11. Address
  12. References

Treatment for FMF is based on the prevention of the painful attacks and the development of amyloidosis (Table 4). Prophylactic therapy with colchicine represents the mainstay of treatment since 1972, when Stephen E. Goldfinger at Harvard Medical School first described the dramatic symptomatic improvement in five patients with FMF treated with colchicine [31]. Other therapeutic – nonconventional – options have been investigated. IL-1 inhibition might be the treatment option for most patients with colchicine-resistant or colchicine-intolerant FMF.

Table 4. Current therapeutic approaches in symptomatic FMF patients
DrugMechanismNotesReference
  1. Steroids are ineffective in preventing or treating attacks

  2. IL-1, interleukin-1.

ColchicineAntigout and antimitotic agent Prevention and treatment of acute painful attacks, and amyloidosisLifelong 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]

Colchicine

Colchicine 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 antimitotic agent, which decreases leucocyte motility and phagocytosis in inflammatory responses, is recommended to prevent frequency of attacks and amyloidosis [31, 85]. A key role was 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 investigators 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].

image

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

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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 substantially 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 progression 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. clarithromycin, 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 colchicine in children with FMF [90]. Adverse effects of colchicine include abdominal pain, nausea, vomiting, diarrhoea, haematological 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 colchicine [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 colchicine unresponsiveness are poorly understood, so far. Either decreased gastrointestinal absorption or decreased intraleucocyte concentration might be potentially involved [96, 97].

Further studies are required to establish whether i.v. colchicine (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 colchicine 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 (NSAIDs) should be considered for the treatment of pain (e.g. i.m. diclofenac) [1].

Anakinra

Anakinra 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.

Rilonacept

In colchicine-resistant or colchicine-intolerant patients with FMF, rilonacept, an IL-1 decoy receptor, has been tested in a 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 Ashkenazi 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. Rilonacept significantly reduced the frequency of FMF attacks by 76% and was better (39%) than the 3-month course with placebo [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

  1. Top of page
  2. Abstract
  3. Introduction
  4. Genetics and pathophysiology of FMF
  5. Diagnosis
  6. Therapy
  7. Prognosis, prevention and screening
  8. Follow-up
  9. Conclusions
  10. Acknowledgements
  11. Address
  12. References

Mortality due to nephrotic syndrome secondary to AA amyloidosis was frequent before the institution of colchicine therapy 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 programme 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 laboratories 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 colchicine treatment should be started when patients are symptomatic [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 that genetic mutations not identified yet are responsible for symptoms.

Follow-up

  1. Top of page
  2. Abstract
  3. Introduction
  4. Genetics and pathophysiology of FMF
  5. Diagnosis
  6. Therapy
  7. Prognosis, prevention and screening
  8. Follow-up
  9. Conclusions
  10. Acknowledgements
  11. Address
  12. References

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 including heavy sports activity should be ruled out. If proteinuria is confirmed, the daily dose of colchicine need to be increased.

Conclusions

  1. Top of page
  2. Abstract
  3. Introduction
  4. Genetics and pathophysiology of FMF
  5. Diagnosis
  6. Therapy
  7. Prognosis, prevention and screening
  8. Follow-up
  9. Conclusions
  10. Acknowledgements
  11. Address
  12. References

Despite FMF is deemed as a rare inherited condition worldwide, it achieves remarkably high prevalence in some populations with Mediterranean ancestors. Historical and geographical factors 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 complex 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

  1. Top of page
  2. Abstract
  3. Introduction
  4. Genetics and pathophysiology of FMF
  5. Diagnosis
  6. Therapy
  7. Prognosis, prevention and screening
  8. Follow-up
  9. Conclusions
  10. Acknowledgements
  11. Address
  12. References

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

  1. Top of page
  2. Abstract
  3. Introduction
  4. Genetics and pathophysiology of FMF
  5. Diagnosis
  6. Therapy
  7. Prognosis, prevention and screening
  8. Follow-up
  9. Conclusions
  10. Acknowledgements
  11. Address
  12. References

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).

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Genetics and pathophysiology of FMF
  5. Diagnosis
  6. Therapy
  7. Prognosis, prevention and screening
  8. Follow-up
  9. Conclusions
  10. Acknowledgements
  11. Address
  12. References