Periodic Fever Syndromes (PFS) are a group of rare, non-infectious disorders characterized by recurrent episodes of fever and systemic inflammation. These conditions are not caused by infection or by a malfunction of the adaptive immune system, distinguishing them from typical autoimmune diseases. The episodes often recur at predictable intervals, and patients typically experience complete health between attacks. PFS are increasingly recognized as a specific category of inflammatory disease, often with a genetic basis.
Understanding Autoinflammation
The fundamental cause of Periodic Fever Syndromes (PFS) is a malfunction within the body’s innate immune system, known as autoinflammation. The innate immune system is the body’s first line of defense, designed to recognize general danger signals. In autoinflammatory disorders, this system becomes dysregulated and triggers an inflammatory response without an external threat or infection.
This mechanism differs significantly from autoimmune disorders, which involve the adaptive immune system mistakenly attacking healthy tissue. PFS do not typically involve the production of autoantibodies or antigen-specific T-cells. Instead, the core issue is the inappropriate activation of inflammatory pathways, often involving a protein complex called the inflammasome.
This dysregulation leads to the overproduction of specific signaling molecules, or cytokines. Interleukin-1 beta (IL-1\(\beta\)) is a potent proinflammatory cytokine that plays a major role in driving the systemic inflammation seen in many PFS. Understanding this molecular pathway has been instrumental in developing targeted treatments.
Recognizing the Recurring Symptoms
The defining feature of PFS is the periodicity of the symptoms, where episodes of high fever recur at regular or irregular intervals. During an attack, the fever can spike abruptly and often lasts for one to seven days, depending on the specific syndrome. The time between these febrile episodes can vary greatly, ranging from weeks to months or even years.
The fevers are typically accompanied by a range of inflammatory symptoms that reflect systemic involvement. Common manifestations include joint pain and swelling (arthralgia or arthritis), and abdominal pain that may mimic conditions like appendicitis. Patients often develop characteristic skin rashes, such as erysipelas-like erythema, or painful mouth sores (aphthous ulcers).
Other symptoms frequently include headaches, muscle aches (myalgia), and inflammation of the lining of internal organs (serositis), which can cause chest or abdominal discomfort. A significant marker during these attacks is the elevation of acute-phase reactants in the blood, such as C-reactive protein (CRP) and Erythrocyte Sedimentation Rate (ESR), indicating high levels of systemic inflammation.
Major Types of Periodic Fever Syndromes
Periodic fever syndromes encompass several distinct conditions, including Familial Mediterranean Fever (FMF) and PFAPA syndrome. FMF is the most frequently diagnosed genetic recurrent fever syndrome, predominantly affecting people of Mediterranean, Middle Eastern, and Armenian descent. It is caused by mutations in the MEFV gene, which encodes the protein pyrin, and is characterized by short attacks of fever, serositis, and joint pain, typically lasting one to three days.
PFAPA (Periodic Fever, Aphthous Stomatitis, Pharyngitis, and Adenitis) syndrome is the most common periodic fever syndrome in children, usually starting between two and five years of age. This syndrome is defined by recurrent fevers, a sore throat (pharyngitis), mouth sores, and swollen lymph nodes in the neck. PFAPA lacks a clear genetic cause, and episodes tend to occur with regularity, often every three to six weeks.
Two other hereditary forms are Tumor Necrosis Factor Receptor-Associated Periodic Syndrome (TRAPS) and Hyperimmunoglobulin D Syndrome (HIDS), also known as Mevalonate Kinase Deficiency (MKD). TRAPS is caused by a mutation in the TNFRSF1A gene and often presents with longer-lasting fever episodes, sometimes persisting for more than one week, along with a migratory skin rash and periorbital edema. HIDS/MKD is a genetic disorder that typically begins in the first year of life, featuring attacks that include high fever, gastrointestinal symptoms, and painful lymph node swelling.
Confirmation and Treatment Strategies
Diagnosis of Periodic Fever Syndromes begins with ruling out common causes of recurrent fever, such as infections and malignancies. Physicians use clinical diagnostic criteria, a detailed patient history documenting the pattern of fever and associated symptoms, and a physical examination. Inflammatory markers, particularly CRP and ESR, are monitored, as they are highly elevated during an attack but return to normal levels in the symptom-free interval.
Genetic testing is essential for hereditary syndromes like FMF, TRAPS, and HIDS/MKD to confirm a mutation in the relevant gene. The primary goals of treatment are to reduce the frequency and severity of inflammatory attacks and to prevent long-term complications, such as the buildup of amyloid protein in organs like the kidneys. Treatment approaches vary based on the specific syndrome.
For FMF, colchicine is the standard long-term treatment, reducing the frequency of attacks and preventing amyloidosis. PFAPA is often managed with a single dose of corticosteroids at the onset of an attack to abort the episode, or sometimes with medications like colchicine or cimetidine to prevent recurrence. For severe or non-responsive cases, particularly those driven by IL-1\(\beta\) overproduction like TRAPS and HIDS/MKD, targeted biologic therapies such as IL-1 inhibitors (e.g., anakinra or canakinumab) have revolutionized management.