Familial Mediterranean Fever: Symptoms, Types, Causes and Treatment

Familial Mediterranean Fever (FMF) is a fascinating, often challenging disease that affects individuals and families, especially those with roots in the Mediterranean basin. As the most common hereditary autoinflammatory syndrome, FMF stands out not only for its distinctive symptoms, but also for its genetic complexity and evolving treatment landscape. This article provides a comprehensive overview of FMF—its symptoms, types, causes, and the latest in treatment—synthesizing the most up-to-date research and expert consensus.

Symptoms of Familial Mediterranean Fever

Familial Mediterranean Fever is renowned for its unpredictable, recurring attacks that can disrupt daily life and pose serious long-term risks. Recognizing the pattern and diversity of symptoms is crucial for early diagnosis and effective management.

Symptom	Description	Frequency/Severity	Source(s)
Abdominal	Intense pain due to peritonitis	Most common (76–95%)	1 4 6
Fever	High temperature, self-limited	Very common (58–100%)	1 2 4 5 6
Chest Pain	Pleuritis or pericarditis	Common (19–40%), variable	1 2 4 6 8
Arthritis	Monoarthritis, mainly lower limbs	Frequent (28–78%)	1 3 6
Skin	Erysipelas-like erythema, rash	Occasional, sometimes isolated	4 6 8
Prodrome	Mild discomfort before attack	~50% of cases	4
Amyloidosis	Renal complications (proteinuria, failure)	Main long-term risk	2 3 5 6
Vasculitis	IgA vasculitis, PAN, Behçet's-like	Rare but notable	9

Table 1: Key Symptoms

The Core Symptoms: Patterns and Manifestations

FMF typically presents as sudden, short-lived episodes of inflammation, with fever and severe pain being the hallmarks. Attacks often last 24–48 hours and resolve spontaneously, leaving patients symptom-free between episodes 6.

Abdominal pain is the most frequent symptom, often signaling peritonitis and experienced by up to 95% of patients. Fever tends to accompany these attacks, sometimes as the only symptom 1 4 6. Chest pain—resulting from pleuritis or, less commonly, pericarditis—occurs in about 20–40% of cases 1 2 6 8.

Arthritis is also common, usually as monoarthritis affecting the knees or ankles. These joint attacks are brief but can recur and, rarely, persist 3 6. Skin symptoms, notably erysipelas-like erythema, may either accompany attacks or appear independently 4 6.

Prodromal Phase and Additional Features

Roughly half of affected individuals notice a prodrome: mild discomfort or vague pain before a full-blown attack. Some also report headaches or rashes at the onset 4.

Long-term complications, particularly amyloidosis, represent the gravest risk. If untreated, amyloidosis can progress to chronic kidney disease and renal failure 2 3 5 6. Less frequently, FMF patients develop certain types of vasculitis, such as IgA vasculitis or polyarteritis nodosa (PAN), sometimes with atypical presentations 9.

Symptom Variability

Not all patients experience every symptom, and attacks may vary in frequency and intensity. Even within the same family, the disease can run a mild or severe course, highlighting the influence of both genetic and environmental factors 2 8.

Types of Familial Mediterranean Fever

Understanding the types (or phenotypes) of FMF helps characterize its clinical course and guide management. FMF is not a one-size-fits-all disease; its presentations exist on a spectrum from classic to silent forms.

Type	Distinguishing Features	Amyloidosis Risk/Manifestation	Source(s)
Type 1	Recurrent acute attacks (fever, serositis)	Risk develops over time	2 6 8
Type 2	Amyloidosis as first/only symptom	Amyloidosis at onset	2 6 8
Type 3	Two mutations, no symptoms ("silent FMF")	No amyloidosis or attacks	8
FMF-like	Mild/incomplete, often in heterozygotes	Variable	8

Table 2: Types of FMF

Type 1: Classic FMF

Type 1 FMF is the most recognized form, marked by recurrent, short episodes of fever and serositis (inflammation of the abdominal lining, chest cavity, or joints). Over time, affected individuals may develop amyloidosis if not adequately treated 2 6 8.

Type 2: Amyloidosis-First

Type 2 FMF is less common but clinically significant. Here, amyloidosis is the initial and sometimes only manifestation, occurring in individuals who were previously asymptomatic. These patients may present with proteinuria or renal dysfunction before any classic FMF attacks are recognized 2 6 8.

Type 3: Silent FMF

A newer recognized category, Type 3 refers to individuals who carry two disease-causing MEFV mutations but do not show any symptoms or develop amyloidosis. This "silent" form underscores the complexity of gene expression in FMF 8.

FMF-like Disease

Mild or incomplete FMF symptoms can occur in heterozygous carriers—those with only one MEFV mutation. These cases may have a less typical, milder, or intermittent pattern and are sometimes called "FMF-like" disease. Modifier genes and environmental factors likely contribute to this variability 8.

Causes of Familial Mediterranean Fever

The root of FMF lies in genetics and the innate immune system, specifically involving the MEFV gene and the pyrin protein. However, the pathway from gene mutation to clinical disease is intricate and influenced by multiple factors.

Factor	Description	Clinical Relevance	Source(s)
MEFV Mutations	Mutations in MEFV gene on chromosome 16	Determine risk, severity, type	1 2 3 5 7 8 10 11 12
Pyrin Protein	Regulates inflammation via inflammasome	Dysregulation leads to symptoms	3 5 7 10 11 12
Inheritance	Autosomal recessive, with variable penetrance	Explains familial clustering	2 3 5 6 8 11 12
Modifier Genes	Other genetic/environmental influences	Affect symptom severity	8 12
Evolution	High carrier rates in Mediterranean	Positive selection (plague?)	7

Table 3: Causes and Risk Factors

The MEFV Gene and Pyrin

FMF is primarily caused by mutations in the MEFV gene located on chromosome 16. This gene encodes the protein pyrin, which plays a critical role in controlling the body's inflammatory response via the inflammasome complex. When mutated, pyrin activity is altered, leading to exaggerated inflammation, particularly via increased IL-1β production 3 5 7 10 11 12.

Patterns of Inheritance

FMF is classically inherited in an autosomal recessive manner: two disease-causing mutations (one from each parent) typically result in the full disease. However, recent findings show that some individuals with only one mutation (heterozygotes) can develop symptoms, suggesting incomplete penetrance and the role of additional genetic or environmental modifiers 2 3 5 6 8 11 12.

Common Mutations

The most frequently observed MEFV mutations include M694V, E148Q, M680I, and V726A. Certain mutations, particularly M694V, are associated with more severe disease and higher amyloidosis risk 1. Some mutations may have arisen and been retained in Mediterranean populations due to a survival advantage, possibly by conferring resistance to infections such as plague 7.

Modifier Genes and Environmental Factors

Not all individuals with the same MEFV mutations have identical symptoms. Modifier genes and environmental influences (like infections or stress) help explain the wide variability in FMF expression, even within the same family 8 12.

Treatment of Familial Mediterranean Fever

Treatment aims to reduce the frequency and severity of attacks, prevent amyloidosis, and improve quality of life. Over the past decades, the therapeutic landscape has expanded, offering hope to patients who do not respond to first-line therapy.

Treatment	Use/Indication	Key Considerations	Source(s)
Colchicine	Mainstay, lifelong therapy	Prevents attacks, amyloidosis	2 3 5 11 12 13 14 15
IL-1 Inhibitors	Colchicine-resistant/intolerant	Anakinra, canakinumab, rilonacept	3 12 14 15 16
NSAIDs/Steroids	Adjunct for arthritis/myalgia	Symptom relief, short-term use	14
Other DMARDs	Rare, refractory cases	Limited evidence	14
Monitoring	Proteinuria, compliance, SAA levels	Early amyloidosis detection	2 12 13

Table 4: Treatment Approaches

Colchicine: The Gold Standard

Colchicine is the cornerstone of FMF management. Taken daily, it significantly reduces the frequency and severity of attacks and, crucially, prevents the development of amyloidosis—even in asymptomatic individuals at risk 2 3 5 11 12 13 14 15. Most patients tolerate colchicine well, and it is considered safe during pregnancy and breastfeeding 14.

Colchicine is recommended lifelong, especially for those with severe genotypes (like M694V/M694V or compound heterozygotes) and for anyone with a history or risk of amyloidosis 2 13. Periodic monitoring for proteinuria and adherence is essential, as non-compliance can lead to complications 2 12 13.

IL-1 Inhibitors: Newer Options for Resistant Cases

A minority of patients (5–10%) are either resistant to or intolerant of colchicine. For these individuals, IL-1 inhibitors such as anakinra, canakinumab, and rilonacept have shown effectiveness in controlling inflammation and preventing attacks 3 12 14 15 16. These biologics target the core inflammatory pathway in FMF and can be life-changing for those with refractory disease.

Adjunctive and Supportive Therapies

NSAIDs and corticosteroids may help with joint pain or myalgia during attacks, but are not substitutes for colchicine 14. Other disease-modifying antirheumatic drugs (DMARDs) are rarely needed and have limited supporting evidence 14.

Monitoring and Preventing Complications

Regular follow-up is critical, focusing on:

• Early detection of amyloidosis (by checking for proteinuria)
• Ensuring compliance with therapy
• Adjusting doses for renal or hepatic impairment
• Monitoring for side effects or toxicity 2 12 13 14

In those who develop renal failure due to amyloidosis, standard management includes renal replacement therapies, including transplantation 2.

Conclusion

Familial Mediterranean Fever is a complex, inherited disease with a broad spectrum of symptoms, types, and outcomes. Advances in genetics and immunology have deepened our understanding and improved management, offering hope for affected individuals and families.

Key Points:

• FMF is characterized by recurrent fever, abdominal and chest pain, arthritis, and skin manifestations, with potential for serious complications like amyloidosis 1 2 3 6.
• Three main types exist: classic (type 1), amyloidosis-first (type 2), and silent (type 3); milder forms may occur in heterozygotes 2 6 8.
• The disease is caused by mutations in the MEFV gene, altering the function of the pyrin protein and leading to dysregulated inflammation 3 5 7 10 11 12.
• Lifelong colchicine is the main treatment, preventing attacks and amyloidosis in most patients. IL-1 inhibitors are reserved for colchicine-resistant/intolerant cases 2 3 5 11 12 13 14 15 16.
• Early diagnosis, consistent therapy, and regular monitoring are essential to prevent complications and optimize quality of life.

Familial Mediterranean Fever continues to be a model for understanding autoinflammatory diseases, offering insights into the intricate dance between our genes, immune system, and environment.