Ethnicity

FMF occurs most commonly, but not exclusively, in populations originating in the Eastern Mediterranean, most notably Arabs, Armenians, Turks, Sephardic and Ashkenazy Jews. The spread of these genetic traits followed the migratory paths of these populations diffusing them broadly to North Africa and the southern European countries, and eventually westward to North and South America. The total number of worldwide cases is unknown but is estimated to be between 100,000 – 500,000. Today FMF has a presence around the world, even in places distant from the Middle East such as Japan, India and Australia. While Middle Eastern ancestry remains a risk factor, FMF can neither be ruled in or out on the basis of a patient’s apparent ethnicity.

Symptoms

The symptoms of FMF can first appear at any age, but are most commonly noted in early childhood and less frequently at older ages; 80% of cases are diagnosed before 10 years of age, 90% before 20 years. But FMF may not be as accurately diagnosed in older patients, and its relative frequency may be disproportionately underestimated in this group.

Recurrent fevers are the most recognized symptom of FMF which explains why it is sometimes called “periodic fever syndrome.” Fevers can be high or low grade and they can recur several times a month or fewer than once per month and last 1‐3 days.

Recurrence of FMF inflammatory attacks

Fevers usually accompany other inflammatory symptoms. Classic symptoms are characterized by episodes or “attacks” of extreme abdominal pain (sterile peritonitis) with recovery in‐between attacks. The attacks vary in frequency and can be as often as once per week or as infrequent as a few times per year or less. Although the most common symptoms involve abdominal pain and fever, the inflammatory targets of FMF are the “serous” membranes which form the lining of body cavities and joints and surround major organs. Inflammatory episodes can involve any of these membranes resulting in pleuritis (thoracic pain), pericarditis (pain around the heart), synovitis (joint pain) and as stated above, peritonitis (abdominal pain). When the joints are involved, inflammation is asymmetrical and can shift from one joint to another, distinguishing it from the symptoms of rheumatoid arthritis. Skin rashes may also occur, particularly in patients with joint involvement; and rashes may be located on the ankles or lower legs. However, there is great variability in the combination of symptoms in different patients as well as the evolution of symptom patterns over time.

The most serious manifestation of FMF, experienced by a small percent of patients, is amyloidosis. Amyloid is a sticky protein that is a product of severe inflammation which adheres to internal organs, most often the kidneys. In advanced cases it can shut them down. Amyloidosis is the most life‐threatening symptom of FMF and can be asymptomatic until it has reached an advanced stage. For this reason, early diagnosis and treatment of FMF is crucial to the long‐term health of FMF patients.

Although the occurrence of acute inflammatory episodes is characteristic of FMF, persistent inflammatory symptoms may be present between attacks in some patients, such as joint pain, body aches, fatigue. But there is great variability of symptoms in different patients and the individual symptoms can look like many other conditions making diagnosis a challenge. Although the symptoms can first appear at almost any age, once symptoms are established, FMF is considered to be a lifetime condition. However, a small number of patients (33 out of 1,000 diagnosed cases in one study) report a sustained remission of symptoms for yet to be understood reasons.

Inheritance

Our understanding of the inheritance mechanism of FMF has continued to evolve since 1992 when researchers first identified the MEFV gene as the location of the genetic cause of FMF. Early research indicated an “autosomal recessive” inheritance pattern, meaning that the disease could arise in children who inherited two FMF mutations – one from each parent. Further genetic research reveals a picture that has grown continuously more complex and cannot be fully characterized by a single, autosomal recessive inheritance model. Hundreds of mutations have been identified in the MEFV gene, some associated with clinical disease and some of unknown clinical significance.

It is now recognized that some patients with a full spectrum of clinical symptoms meeting established diagnostic criteria for FMF have only one mutation in the MEFV gene, indicating that “autosomal recessive” is not the only way that FMF is inherited. A common error in the interpretation of genetic results is to categorize a patient with one mutation in the MEFV gene as a “carrier” – meaning that the patient does not have FMF because two mutations are required. Not only can a single MEFV mutation be associated with a correct diagnosis of FMF, there are FMF patients, correctly diagnosed by established criteria, who have no mutations in the MEFV gene. These patients are classified as “FMF mutation negative.” Such cases imply that there are mutations in other genes that can produce the clinical manifestations of FMF; potential candidates would be mutations associated with other autoinflammatory disorders, among which there is significant overlap of inflammatory symptoms.

Another complicating factor is that FMF patients are at risk of having more than one autoinflammatory disorder. The chance of full characterization of the patient’s genetic status depends on the scope of the genetic test. There are a variety of genetic tests ranging from very narrow (testing for a short list of specific mutations in one gene) to very broad (sequencing whole genes or whole sections of the genome or even the entire genome). A patient classified as “FMF mutation negative” may not have had a genetic test broad enough to identify the relevant disease‐associated mutations. “FMF panel” tests were the earliest tests available, testing for as few as a dozen specific mutations in the MEFV gene. Genetic testing itself has rapidly advanced and has become more comprehensive, but there remains inconsistency in the tests available and the scope of what they test for. While genetic results are helpful in narrowing the genetic pathology, identifying genetic risk factors for the most serious disease manifestations, and understanding familial inheritance patterns, they are not the sole determining factor in establishing a diagnosis. There remains yet much to be discovered regarding the genetic underpinnings of FMF and the other auto‐inflammatory disorders.

Diagnosis and Treatment

A correct diagnosis is of primary importance and is essential for effective treatment. Because the inflammatory symptoms of FMF can look like many other conditions, misdiagnosis is common. Misdiagnosis is serious because it leads to inappropriate, ineffective and in some cases harmful treatments. There are three factors that contribute to a diagnosis of FMF: the pattern of symptoms/clinical observations, mutations found in the MEFV gene, a positive response to colchicine.

The established diagnostic criteria are the Tel Hashomer criteria. (figure to the right)

Livneh A, Langevitz P, Zemer D, Zaks N, Kees S, Lidar T, et al. Criteria for the diagnosis of familial Mediterranean
fever. Arthritis Rheum 1997;40:1879–85.

If symptoms are consistent with FMF, then it is a positive response to colchicine that will confirm the diagnosis. This is a significant point. Negative genetic results should not rule out a colchicine trial because response to colchicine is the determining diagnostic factor, not genetic results.

Genetic results can support an FMF diagnosis if mutations are found in the MEFV gene. They can help identify some patients who might be at risk of amyloidosis, and they provide a tool for testing other family members. But genetic results can be complex and difficult to interpret because hundreds of mutations have been found in the MEFV gene, not all of which have effects that are presently understood.

Colchicine is the gold‐standard treatment and has unique therapeutic benefits for FMF. Colchicine dramatically reduces the acute inflammatory symptoms of FMF and prevents the development of amyloidosis in the subset of FMF patients at risk of this life‐threatening manifestation. Colchicine has been shown to restore the quality of life to FMF patients and has increased the longevity of FMF patients to that of the general population. So the first step in treatment is to make every effort for successful treatment with colchicine. This may involve trying more than one brand of colchicine since there is brand variability in patients’ response. It is worth some trial‐and‐error effort to achieve a positive response because colchicine is preferable to alternative treatments.

In a small number of cases, even after trying 3 brands of colchicine, there are patients who have only a partial response to colchicine, no response or adverse response. These patients may be treated with a class of drug that is an interleukin‐1 inhibitor, which selectively targets the faulty inflammatory mechanism at the heart of FMF and auto‐inflammatory pathology. These drugs have been shown to be effective in the few patients who do not respond to colchicine. Most frequent of the IL‐1 inhibitors prescribed to FMF patients are Kineret (anakinra) a short acting drug, and Ilaris (canakinumab) a long acting drug. Access to these drugs can be limited by their high cost. Insurers may set a high bar of diagnostic and clinical evidence before approving coverage.

FMF is a generally treatable disorder in which most patients can attain a high degree of symptom control and quality of life. The highest hurdle, however, is the first one: an accurate diagnosis. FMF must be correctly diagnosed to be correctly treated. Because of its rarity, the medical community has a low awareness of it and it is common for patients to have a long history of misdiagnosis (and in many cases unnecessary surgery) before the correct diagnosis is found.

There is great symptomatic variability in FMF as well as symptomatic overlap across the autoinflammatory disorders. There is also a possibility that a patient can have more than one autoinflammatory disorder. If a diagnosis of FMF is under consideration, it is worthwhile to take the spectrum of autoinflammatory disorders into consideration. A concise yet comprehensive resource for comparing and contrasting the autoinflammatory disorders has been developed and refined by the Autoinflammatory Alliance and can be found at this link: http://www.nomidalliance.org/compchart.php