Periodic Fever Syndrome
Periodic Fever Syndromes (PFS), also known as autoinflammatory syndromes, are a group of rare, hereditary or sporadic disorders characterized by recurrent episodes of fever and systemic inflammation in the absence of infection or autoantibody production. The pathogenesis of these syndromes is primarily linked to dysregulation of the innate immune system, particularly involving the overproduction or aberrant regulation of pro-inflammatory cytokines such as interleukin-1 (IL-1). Mutations in genes encoding proteins that regulate inflammation, such as MEFV, NLRP3, TNFRSF1A, and MVK, are commonly implicated, leading to inappropriate activation of the inflammasome and excessive cytokine release. Clinically, these syndromes manifest with recurrent fevers often accompanied by symptoms such as rash, serositis, arthralgia, abdominal pain, and in some cases, amyloidosis, which can result in significant morbidity and potential mortality if left untreated. The impact on health varies depending on the specific syndrome, frequency and severity of attacks, and the risk of long-term complications such as renal amyloidosis.
Familial Mediterranean Fever is an autosomal recessive disorder most prevalent among individuals of Mediterranean descent, including those of Armenian, Turkish, Arab, and Jewish ancestry. It is caused by mutations in the MEFV gene encoding pyrin, leading to uncontrolled activation of the inflammasome and excessive IL-1β production. FMF is characterized by recurrent episodes of fever lasting 1–3 days, accompanied by serositis (peritonitis, pleuritis, or pericarditis), arthritis, and erysipelas-like erythema. The most severe complication is the development of AA amyloidosis, particularly affecting the kidneys.
TRAPS is an autosomal dominant disorder resulting from mutations in the TNFRSF1A gene, which encodes the tumor necrosis factor receptor 1. It is characterized by prolonged febrile episodes lasting up to several weeks, with associated symptoms such as migratory myalgia, abdominal pain, rash, conjunctivitis, and periorbital edema. The inflammatory episodes are less frequent but more protracted than in other periodic fever syndromes, and there is a risk of developing secondary amyloidosis.
CAPS encompasses a spectrum of disorders caused by mutations in the NLRP3 gene, leading to constitutive activation of the cryopyrin inflammasome and excessive IL-1β release. The spectrum includes Familial Cold Autoinflammatory Syndrome (FCAS), Muckle-Wells Syndrome (MWS), and Neonatal-Onset Multisystem Inflammatory Disease (NOMID)/Chronic Infantile Neurological Cutaneous Articular Syndrome (CINCA). Clinical manifestations range from cold-induced urticaria and fever to progressive sensorineural hearing loss, chronic meningitis, arthropathy, and severe systemic inflammation.
MKD/HIDS is an autosomal recessive disorder caused by mutations in the MVK gene, which encodes mevalonate kinase, resulting in impaired isoprenoid biosynthesis and dysregulated inflammatory responses. Patients experience recurrent febrile episodes, often associated with lymphadenopathy, abdominal pain, diarrhea, arthralgia, and a characteristic elevation of serum IgD. Attacks can be triggered by vaccinations or stress, and the severity varies widely.
PFAPA is a non-hereditary, idiopathic syndrome presenting in early childhood with regularly recurring episodes of high fever, aphthous stomatitis, pharyngitis, and cervical adenitis. Each episode typically lasts 3–6 days and recurs every 3–8 weeks. PFAPA is distinguished by its predictable periodicity, absence of significant laboratory abnormalities between attacks, and excellent long-term prognosis, with most patients outgrowing the syndrome by adolescence.
Periodic Fever Syndromes are rare diseases with varying prevalence depending on the specific syndrome and population. Familial Mediterranean Fever (FMF) is the most common, with a prevalence of 1 in 200 to 1 in 1,000 among high-risk Mediterranean populations, while it is much rarer elsewhere. TRAPS has an estimated prevalence of 1 in 1,000,000, and CAPS is extremely rare, with a prevalence of less than 1 in 1,000,000. Mevalonate Kinase Deficiency/Hyper IgD Syndrome is also rare, with several hundred cases reported worldwide. PFAPA is the most common periodic fever syndrome in children in Western countries, with an estimated incidence of 2.3–3.2 per 10,000 children. There is no significant gender predilection for most syndromes, except for a slight male predominance in FMF. Onset is typically in childhood or adolescence, although adult-onset cases are increasingly recognized. The risk of secondary amyloidosis varies, being highest in FMF and TRAPS, and dependent on genetic and environmental factors, as well as adequacy of treatment.
Diagnosis of Periodic Fever Syndromes is based on a combination of clinical criteria, family history, and, increasingly, genetic testing. A thorough patient history is essential, focusing on the pattern, duration, and frequency of febrile episodes, associated symptoms, and response to treatments. Laboratory evaluation during attacks typically reveals elevated acute phase reactants such as C-reactive protein (CRP) and serum amyloid A (SAA), while findings between attacks are often normal. Specific diagnostic criteria have been developed for each syndrome, such as the Tel Hashomer criteria for FMF, the Eurofever/PRINTO classification criteria for TRAPS, CAPS, and MKD/HIDS, and the Marshall criteria for PFAPA. Genetic testing is increasingly utilized to confirm the diagnosis, identify pathogenic mutations, and guide management, although the absence of a mutation does not exclude the diagnosis in all cases. Exclusion of infectious, neoplastic, and autoimmune etiologies is mandatory. Imaging studies and biopsy may be indicated to assess for complications, such as amyloidosis. Response to empiric therapy, such as colchicine in FMF, can also aid in diagnosis.
Colchicine is widely used as a first-line therapy for Familial Mediterranean Fever, demonstrating efficacy in reducing the frequency and severity of attacks as well as preventing the development of amyloidosis. Canakinumab, a monoclonal antibody targeting interleukin-1β, is indicated for the treatment of several periodic fever syndromes, including CAPS, TRAPS, and MKD/HIDS, and is administered as a subcutaneous injection to reduce inflammation and the frequency of febrile episodes. Rilonacept, an interleukin-1 cytokine trap, acts by binding and neutralizing IL-1 and is approved for use in patients with CAPS to control systemic and organ-specific inflammatory manifestations. Anakinra, a recombinant IL-1 receptor antagonist, is also utilized in the management of various periodic fever syndromes, particularly CAPS and refractory cases of other autoinflammatory conditions, offering rapid symptom relief by inhibiting IL-1–mediated pathways.
| Structure | Generic Name | CAS Registry Number | Molecular Formula | Molecular Weight |
|---|---|---|---|---|
| canakinumab (Prop INN; USAN) | 914613-48-2 | |||
 | colchicine | 64-86-8 | C22 H25 N O6 | 399.437 |
| IL-1 cytokine Trap; interleukin-1 Trap; rilonacept (Rec INN; USAN) | 501081-76-1 | |||
| anakinra (Rec INN; USAN) | 143090-92-0 |
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