Familial Mediterranean Fever: Assessing the Overall Clinical Impact and Formulating Treatment Plans
Raffaele Manna1,2 and Donato Rigante3,2..
Received: January 14, 2019
Accepted: March 7, 2019
Mediterr J Hematol Infect Dis 2019, 11(1): e2019027 DOI 10.4084/MJHID.2019.027
This is an Open Access article distributed
under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by-nc/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
Abstract Recurrent
self-limited attacks of fever and short-lived inflammation in the
serosal membranes, joints, and skin are the leading features of
familial Mediterranean fever (FMF), the most common autoinflammatory
disorder in the world, transmitted as autosomal recessive trait caused
by MEFV gene mutations. Their
consequence is an abnormal function of pyrin, a natural repressor of
inflammation, apoptosis, and release of cytokines. FMF-related mutant
pyrins are hypophosphorylated following RhoA GTPases’ impaired activity
and show a propensity to relapsing uncontrolled systemic inflammation
with inappropriate response to inflammatory stimuli and leukocyte
spread to serosal membranes, joints or skin. Typical FMF phenotype 1
consists of brief episodes of inflammation and serositis, synovitis,
and/or erysipelas-like eruption, whereas phenotype 2 is defined by
reactive amyloid-associated (AA) amyloidosis, which is the most ominous
complication of FMF, in otherwise asymptomatic individuals. |
Introduction
The Ancient Heredity of Familial Mediterranean Fever
The Size of a Borderless Disease
Pyrin, an Intracellular Sentinel against Infections
A Host of Genotype Studies
A Kaleidoscopic Disease with Protean Faces
Abdominal pain, due to peritoneum inflammation resembling acute abdominal disease like appendicitis, cholecystitis, ureteral stones or pelvic inflammatory disease, is present in about 90% of patients and is frequently associated with small amounts of ascites upon ultrasound investigation. Peritoneum inflammation may also occur in the form of massive ascites with myofibroblast proliferation in the mesenteric region as an initial presentation of FMF.[50] Sometimes (in 30-40% of cases) patients might undergo unnecessary surgery.[51] Unilateral or bilateral pleural effusion can be demonstrated in 50-60% of patients and is characterized by quick resolution, while recurrent pericarditis can be observed in a small percentage of FMF patients (1-2.5%) during febrile attacks.[52,53] Intense scrotal pain simulating a testicular torsion is frequent in children with FMF, but it usually requires a conservative management.[54] Joint involvement is reported in 45% of cases and might present as transient arthralgia or oligoarthritis: short-lasting attacks begin without prodromes, involve large joints and suddenly disappear after 24-48 hours with no sequelae. Rarely arthritis may last for more than one week or even develop destructive features.[55] Some patients have painful, swollen and self-limited erythematous skin lesions on the legs: these lesions resemble a skin infection called erysipelas and are quite specific for FMF.[56] Another symptom associated with FMF is muscle pain, which might be severe and paralyzing: this muscular involvement is not prevented by colchicine and does not respond to nonsteroidal anti-inflammatory drugs, but only to corticosteroids. Muscular manifestations can present with severe febrile myalgia having three different patterns: spontaneous, effort-induced (i.e., exertional leg pain) and prolonged with an overall duration of 6 weeks.[57,58]
In recent times the clinical spectrum of FMF has expanded and many non-canonical manifestations have been reported.[59] For instance, neurologic signs other than constitutional headache have been described in some FMF patients, such as recurrent aseptic meningitis, demyelinating disorders, recurrent peripheral facial palsy and even stroke.[60]
Amyloidosis is the most dreadful complication of late-diagnosed, untreated or neglected FMF, which results from the deposition in different organs of a fatty-like substance, which is a cleavage product of serum amyloid-A, an acute-phase reactant produced by the liver. Main organs involved by amyloid deposition are kidney, gut, spleen, liver, heart and endocrine glands. Renal amyloidosis culminating in renal failure, which occurs in as many as 60% of untreated patients with FMF, is the major cause of death in FMF. Recent studies have focused on the polymorphism of the SAA1 gene as a genetic contributor to the development of amyloidogenesis, but found no influence by the major histocompatibility complex.[61] The pathogenic role of environmental factors in FMF-related amyloidosis such as the country of origin is suggested by the lower incidence of amyloidosis in Jews living outside the Mediterranean basin: for instance, Armenians living in Armenia have a much higher incidence of amyloidosis than Armenian Americans, even before the introduction of colchicine. In addition, amyloidosis appears to be less common among Iraqis, Ashkenazi Jews and Arabs.[62] The association between amyloidosis and the mutation M694V is widely reported,[63] but non-amyloid glomerulopathies such as IgM or IgA nephropathy, focal and diffuse proliferative glomerulonephritis, and rapidly progressive glomerulonephritis have also been observed. Also, some non-granulomatous vasculitides, such as Henoch-Schönlein purpura (in 2.6-5% of cases), polyarteritis nodosa (0.8-1%) and Behçet’s disease (0.5%) have been associated with FMF.[64-66] Over the years, an increased rate of MEFV carriers has also been found in complex multifactorial diseases such as ankylosing spondylitis and multiple sclerosis, implicating this gene and its pathways in the development of such disorders.[67] A few patients with FMF might also have attacks characterized by macrophage activation syndrome, in which well-differentiated mononuclear cells exhibiting hemophagocytic activity have swarmed different organs and systems, giving rise to a dramatic clinical picture consisting of persistent fever, multi-organ damage, cytopenia, hyperferritinemia, hypertriglyceridemia, and hypofibrinogenemia with high mortality rates.[68,69] Lastly, a retrospective study related to over 8.000 Jewish patients with FMF registered at the Tel Hashomer Hospital (with a mean age of 43.74 ± 14.7 years) revealed that there is a significantly lower incidence of cancer in FMF patients than in the general population of Israel, and which might be attributed to a direct physiologic effect of FMF or the antimitotic effects of colchicine administered on the long run.[70] Table 1 shows the main clinical features reported by 373 patients managed in the Periodic Fevers Research Center of our University.
Table 1. List of the main clinical features of familial Mediterranean fever in the cohort of patients managed in our Centre. |
Searching for Universal Diagnostic Criteria of Familial Mediterranean Fever
In 1997 new criteria were validated by Livneh et al. to corroborate the clinical elements included in the Tel Hashomer criteria, but excluding other manifestations, like amyloidosis not explained by any other causative factor, less common at the onset of FMF. Two versions of these criteria, one more conservative and extensive than the other, were created, both with a sensitivity and specificity above 95%: the presence of at least 1 of 4 major criteria related to “typical” disease attacks or 2 of 5 minor criteria or 1 minor criterion plus 5 of 10 supportive criteria should suggest the diagnosis of FMF (see Table 3).[72]
Diagnosis of FMF in children has been established using the same clinical criteria created for adults. However, a frequent delay in the appearance of a complete clinical picture in very young children, the presence of atypical signs, and absence of a suggestive family history may cause additional difficulty. Moreover, the evidence that some criteria were of poor relevance for children with FMF and differences of some clinical manifestations in younger children (who might have shorter attacks, infrequent chest pain, or even fever alone) prompted a Turkish group of clinicians in 2009 to formulate new FMF criteria for the pediatric population (the so-called Turkish FMF Pediatric criteria), listed in the Table 4.[73] The pediatric cohorts where these criteria were evaluated included only cases genetically ascertained to have two MEFV mutations, regardless of their phenotypes.
These Turkish criteria for the diagnosis of FMF yielded a better sensitivity in an international cohort of children from either European or Eastern Mediterranean regions, though their specificity was lower than in previous criteria.[74] Anyway, all used diagnostic criteria should need further improvements, such as validation on broader cohorts of probands, and the inclusion of genetic data. Federici et al. developed new classification criteria for the diagnosis of different autoinflammatory disorders through the identification of ‘positive’ and ‘negative’ criteria correlated with each disease, suggesting that the presence of aphthous stomatitis, urticaria-like rashes, cervical lymph node enlargement and febrile episodes lasting more than 6 days should exclude the diagnosis of FMF.[75]
There is no specific laboratory examination to support the diagnosis of FMF, except for MEFV analysis. During typical acute attacks, blood tests show a generalized increase of the inflammatory parameters (erythrosedimentation rate, C-reactive protein, serum amyloid-A, immunoglobulins) with a parallel neutrophil leukocytosis (until and over 20.000/mm3).[76]
The role of genetics in supporting the diagnosis of FMF is essential, but the genetic analysis should never substitute both clinical process and clinician’s judgment. Following MEFV cloning, the genetic test for FMF has become available in many countries, providing a new exciting tool for diagnostic confirmation. Genetic diagnosis is definite when two mutations, also nonidentical, are present in the two MEFV alleles; if only one or no pathogenic mutation is found the clinical diagnosis of FMF is still possible due to the potential occurrence of occult mutations. Of course, for patients with typical clinical pictures and appropriate ethnic origin, FMF diagnosis can be made without a genetic confirmation, which is vice versa contributory for cases with atypical presentation, the absence of family history, or unusual ethnic origin. In particular, genetic testing might reveal no known mutation in 30-40% of patients: in this case if clinical manifestations are convincingly those of FMF the patient is put on an open trial with colchicine for 3-6 months. If there is a positive response and symptoms reappear after stopping colchicine, it is assumed that the patient has FMF.[77]
Furthermore, diagnosis of FMF in very young heterozygous children should be made with caution, as FMF heterozygous children can present with an FMF-like disease in early childhood, which does not differ from that seen in patients carrying two mutated alleles, although it may disappear with age. Therefore, a careful follow-up of heterozygous children is of paramount importance before establishing a definite diagnosis.[78] For individuals with two FMF-related mutations who do not report symptoms, if there are risk factors for amyloidosis (such as the country, family history, and persistently elevated inflammatory markers, particularly serum amyloid-A), a close follow-up should be started and at least colchicine prophylaxis considered.
Ancient and Modern Treatments
Complete remission of FMF under colchicine is achieved in 65% of patients and partial remission in 30%, while around 5% of patients remain nonresponsive.[84] True resistance to colchicine is a rare event, mostly observed in patients displaying peculiar MEFV genotypes and occurring despite the regular use of colchicine at the maximal doses. Low adherence to colchicine administration may be a key component of resistance and should be assessed.[85] Since long-term colchicine prophylaxis may be complicated by gastrointestinal side effects, by our experience, we usually recommend lactose-free diet and treatment of intestinal bacterial overgrowth to improve colchicine tolerance.[86] There are also FMF patients with low disease activity who might become utterly free of attacks for a long time and even stop colchicine prophylaxis: long-term remission of FMF, characterized by a time interval of at least 3 years without FMF clinical manifestations and off-colchicine, after a period of FMF activity, is rather infrequent. The prevalence of disease remission in the FMF population is estimated at 3.3%, based on a study by Ben-Zvi et al. from the largest center for diagnosis and treatment of FMF in Israel.[87] These patients seem to have distinct clinical, demographic and molecular characteristics, allocating them to the mildest end of the disease severity spectrum of FMF. This phenotype is comparable to that of patients with late-onset FMF.[88]
FMF protracted arthritis, mostly affecting hip or knees, has shown results following treatment with tumor necrosis factor inhibitors.[89] Characterization and early identification of FMF patients with uncontrolled inflammatory activity have become more important after the availability of new treatment options for the prevention of disease-associated complications and permanent damages of FMF. After the demonstration of inflammasome dysregulation as the dominating pathogenetic mechanism in different autoinflammatory disorders including FMF, IL-1β has been shown as the most intriguing target to attack.[90,91] An increasing experience of IL-1 blockade has been matured over recent times and, after showing its dramatic efficacy in cryopyrin-associated periodic syndrome, a rare and totally IL-1-mediated hereditary autoinflammatory disorder,[92] several case reports and case series dedicated to FMF have documented both efficacy and safety of anti-IL-1 agents, such as anakinra, canakinumab and rilonacept in patients inadequately responding to colchicine.[93-96] All IL-1 inhibitors are effective for controlling attacks and inflammatory activity in patients with refractory FMF and even in those complicated with AA amyloidosis, reducing or stabilizing the amount of proteinuria and preserving renal function in short-term follow-up studies. Structured scores rating FMF activity or severity by the use of attack parameters (site, duration and frequency) have been used to classify and settle disease diversity, while response to treatment has been evaluated by patients’/parents'/physicians' global assessment of disease severity, laboratory parameters performed every 6 months, and different scores related to symptoms and organ damages.[97-102]
How to Put Patients in Differential Diagnosis
General Conclusions
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