Familial Mediterranean fever (FMF)
INTRODUCTION — Familial Mediterranean fever (FMF) is a hereditary autoinflammatory disorder characterized by recurrent bouts of fever and serosal inflammation. This topic will review the clinical manifestations and diagnosis of FMF. The epidemiology, genetics, pathophysiology, and management of FMF and an overview of periodic fever syndromes and other autoinflammatory diseases can be found elsewhere. (See “Familial Mediterranean fever: Epidemiology, genetics, and pathogenesis” and “Management of familial Mediterranean fever” and “The autoinflammatory diseases: An overview”.)
CLINICAL MANIFESTATIONS — Familial Mediterranean fever (FMF) is characterized by sporadic, and in most cases, recurrent attacks of fever and serosal inflammation as manifested by abdominal and chest pain. Most patients with FMF experience their first attack in early childhood. The initial attack occurs before the ages of 10 and 20 years in 65 and 90 percent of cases, respectively [1]. However, in rare cases the initial attack can occur in individuals older than 50 years of age.
The onset of fever and pain (due to serositis at one or more sites) is usually abrupt, peaking soon after onset. Some patients have a stereotypic prodrome before their attacks [2]. This may include various constitutional and physical signs, such as restlessness at the site where the symptom is about to occur, anxiety, irritability, increased appetite, and taste alterations [2]. Episodes last for one to three days and then resolve spontaneously. Patients are asymptomatic between attacks. The frequency of attacks is highly variable, even in a given patient. The intervals between episodes are irregular, ranging from one week to several months or years. Usually, FMF patients cannot describe a consistent triggering event. Nevertheless, vigorous exercise, emotional stress, intercurrent infections, exposure to cold, surgery, and menstruation have been associated with an attack in some patients. During pregnancy, the course of FMF may worsen in about a third of the patients, improve in another third of patients, and remain unchanged in the rest [3].
Recurrent fever — Fever is one of the most constant characteristics of FMF and is present in almost all cases during attacks [4]. In the majority of FMF patients, the temperature rises from 38° to 40°C (100.4° to 104°F), although mild attacks may be accompanied by a subfebrile temperature (37.5° to 38°C or 99.5° to 100.4°F). Typically, the duration of the fever is brief, lasting between 12 hours and three days. Fever may be the first and only symptom of FMF, especially in toddlers [5]. In FMF patients who are treated with colchicine, an acute attack may occur without fever.
Abdominal pain — In Middle-Eastern populations where FMF is common, up to 95 percent of the patients with FMF have episodic abdominal pain [1]. In patients from Europe and Japan, this rate is much lower (less than 80 percent) [6,7]. Abdominal pain and tenderness may initially be localized and then progress to become more generalized. Since the cause of the abdominal pain is inflammation of the peritoneum, signs of peritonitis such as guarding, rebound tenderness, rigidity, and an adynamic ileus are often present. These findings can be mistaken for an acute surgical abdomen leading to diagnosis delay and sometimes even to futile operations. (See “Evaluation of the adult with abdominal pain”, section on ‘Urgent/emergent evaluation and/or surgical abdomen’ and “Causes of acute abdominal pain in children and adolescents” and “Emergency evaluation of the child with acute abdominal pain”.)
Chest pain — Painful FMF attacks are localized to the chest in 33 to 84 percent of patients, depending on the patient’s ethnic origin [4]. Armenian FMF patients are reported to have a higher rate of pleuritic involvement compared with other ethnic groups. Chest pain may be due to inflammation of the pleura or referred pain from subdiaphragmatic inflammation. Pleural inflammation typically manifests as unilateral chest pain that is worse with inspiration or coughing. Patients often have a small, transient pleural effusion. Episodes usually resolve within three days, but may last up to one week. Concomitant pericarditis can also be observed in patients with pleuritis.
Joint pain — Among non-Ashkenazi Jews with FMF, approximately 75 percent experience sudden attacks of articular pain, which may be precipitated by minor trauma or effort such as prolonged walking. The joint attacks are usually monoarticular, involving one of the large joints (knee, ankle, hip). In rare cases, patients present with a migratory polyarthritis. Gradual resolution of the signs and symptoms occur after peaking in 24 to 48 hours. The synovial fluid analysis is typically sterile, with a nucleated white cell count ranging from 200 to >100,000 white blood cells/mm3 [8]. The synovitis usually resolves completely without leading to joint destruction. However, severely protracted cases can result in permanent deformity, functional limitation, osteoporosis around the affected joint, and aseptic necrosis [9]. The arthritis may occasionally last for weeks to months, or evolve into a more chronic form of arthritis. (See “Synovial fluid analysis” and “Clinical manifestations, diagnosis, and evaluation of osteoporosis in postmenopausal women” and “Treatment of nontraumatic hip osteonecrosis (avascular necrosis of the femoral head) in adults”.)
Erysipelas-like skin lesion — An erysipelas-like skin lesion is reported in 12 to 40 percent of FMF patients [10]. The lesion is typically 10 to 35 cm2 in area, tender, raised, and erythematous and occurs on the lower leg, ankle, or foot (picture 1). Lesions may be transiently warm without associated pain or tenderness. Erysipelas-like skin lesions may be the presenting feature of FMF in children and may be misdiagnosed as an infectious erysipelas or cellulitis [11,12]. Children with myalgia and erysipelas-like skin lesions during attacks are at increased risk for subclinical inflammation during attack-free intervals, as evidenced by elevation of acute phase reactants [13]. Recovery is spontaneous and does not require antibiotics. (See ‘Laboratory findings’ below and “Cellulitis and skin abscess: Epidemiology, microbiology, clinical manifestations, and diagnosis”.)
Other manifestations — Other rare manifestations of FMF include the following:
●Exertional myalgia – Exercise-induced myalgia is a typical manifestation of FMF. It usually affects the lower limbs (thighs and calves) in children with the disease. It does not have an episodic characteristic and is not controlled by treatment with colchicine. It resolves with rest or treatment with nonsteroidal anti-inflammatory drugs (NSAIDs). (See “Management of familial Mediterranean fever”, section on ‘Exertional myalgia’.)
●Acute pericarditis – Symptomatic acute pericarditis occurs in less than one percent of patients with FMF [14]. In one study, the frequency of pericarditis was found to be 11-fold higher than in the general population [15]. However, even in FMF, acute pericarditis is still a rare event. Clinical features of pericarditis include chest pain (sharp and pleuritic, improved by sitting up and leaning forward), pericardial friction rub, and widespread ST segment elevation on electrocardiogram [15]. The length of such an attack is similar to that of any typical FMF attack. Usually, recurrent attacks of FMF pericarditis do not lead to constrictive pericarditis. (See “Acute pericarditis: Clinical presentation, diagnostic evaluation, and diagnosis”.)
●Acute scrotum – In children with FMF, acute scrotum is characterized by mostly unilateral painful and swollen scrotum. Operative findings show normal testes and epididymis and a thick and hyperemic tunica vaginalis. Acute scrotum should be differentiated from testicular torsion and does not require surgical intervention. Acute scrotal swelling and tenderness due to orchitis is a rare manifestation of FMF [10,16]. (See “Acute scrotal pain in adults”.)
●Protracted febrile myalgia – Patients with FMF can present with protracted bouts of febrile myalgia that can last up to eight weeks. Febrile myalgias usually involve the lower extremities but, in some cases, may be more diffuse [17]. Patients with febrile myalgia have an increased erythrocyte sedimentation rate but a normal serum creatine kinase level and a normal electromyogram (EMG). Protracted febrile myalgia is associated with severe course of FMF and homozygosity for M694V mutation. Although the etiology is not clear, febrile myalgia is considered to be a vasculitic manifestation of FMF. However, in none of muscle biopsies taken from these patients could frank vasculitis be shown [18]. (See “Management of familial Mediterranean fever”, section on ‘Management of specific features’.)
●Headache and aseptic meningitis – Headache may accompany acute FMF attacks and are usually mild. A more severe type of headache in the form of recurrent aseptic meningitis has also been reported, but it is still unclear whether this clinical feature is part of FMF [19]. (See “Aseptic meningitis in adults”.)
●Rash and oral ulcers – Skin rash and oral ulcers have been reported in European and Japanese patients [6,20]. These are not typical features of FMF and may present patients with other autoinflammatory diseases (tumor necrosis factor [TNF] receptor-1 associated periodic syndrome [TRAPS], cryopyrin-associated periodic syndrome [CAPS], and mevalonate kinase deficiency [MKD]) who were wrongly diagnosed with FMF. Very rarely, skin rash may be seen in cases of atypical FMF [7]. (See “The autoinflammatory diseases: An overview”.)
●Associated diseases – Systemic nongranulomatous vasculitides such as immunoglobulin A vasculitis (IgAV; Henoch-Schönlein purpura [HSP]), classical polyarteritis nodosa, ankylosing spondylitis, and Behçet syndrome have a higher incidence among FMF patients [21,22]. However, the possibility that diseases such as IgAV (HSP) or polyarteritis nodosa, which occur in FMF patients, are actually rare manifestations of FMF has also been suggested [23]. In most of these cases, the patients carry at least a single M694V mutation in the MEFV gene. (See “IgA vasculitis (Henoch-Schönlein purpura): Clinical manifestations and diagnosis” and “Clinical manifestations and diagnosis of polyarteritis nodosa in adults” and “Clinical manifestations and diagnosis of Behçet syndrome”.)
LABORATORY FINDINGS — Acute attacks of FMF are accompanied by elevation of serum markers of systemic inflammation. Common laboratory findings include leukocytosis with a predominance of neutrophils as well as elevated acute phase reactants such as the erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), serum amyloid A (SAA) protein, and fibrinogen. Serum homocysteine and lipoprotein(a) concentrations are often increased in individuals with FMF during attack-free periods. The presence of otherwise unexplained proteinuria in between attacks is suggestive of renal amyloidosis. However, FMF patients with proteinuria who are treated with colchicine should be evaluated for causes other than amyloidosis. (See “Renal amyloidosis”.)
LONG-TERM COMPLICATIONS
Secondary (AA) amyloidosis — Progressive secondary (AA) amyloidosis is a major cause of mortality in patients with familial Mediterranean fever (FMF) [24]. Rarely, patients can present with renal amyloidosis as the first and only manifestation of FMF [25]. Patients with renal amyloidosis can present with asymptomatic proteinuria or clinically apparent nephrotic syndrome and gradually develop progressive nephropathy with end-stage kidney disease. End-stage kidney disease develops 2 to 13 years after the onset of proteinuria [1]. Amyloid deposition can also occur in the spleen, liver, and gastrointestinal tract and subsequently in the heart, thyroid, and testes. Patients with gastrointestinal tract amyloidosis usually present with diarrhea and malabsorption. The clinical manifestations of amyloidosis are discussed in detail, separately. (See “Overview of amyloidosis”
