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name: Familial Mediterranean Fever
creation_date: '2025-12-04T16:57:31Z'
updated_date: '2026-04-22T20:53:03Z'
category: Genetic
parents:
- Autoinflammatory Disease
- Inherited Disorder
has_subtypes:
- name: Type 1
description: Classic form presenting with recurrent episodes of fever and serositis.
evidence:
- reference: PMID:25649364
reference_title: "Familial Mediterranean Fever."
supports: NO_EVIDENCE
snippet: Familial Mediterranean Fever is an autosomal recessive inherited disease with a course of autoinflammation, which is characterized by the episodes of fever and serositis.
explanation: Although the literature describes Familial Mediterranean Fever having episodic fever and serositis, it does not define subtypes or a 'Type 1' specifically.
- reference: PMID:23823268
reference_title: "A taste of periodic fever syndromes."
supports: NO_EVIDENCE
snippet: Periodic fevers are acquired or inherited disorders of innate immunity, which were first described in the 1940s. ... This clinical review focuses on a sample of autoinflammatory disorders including familial Mediterranean fever...
explanation: There is a general discussion of Familial Mediterranean Fever but no mention of subtypes or a classification system involving the term 'Type 1'.
- reference: PMID:36889987
reference_title: "MEFV gene mutation spectrum in patients with familial mediterranean fever."
supports: NO_EVIDENCE
snippet: MEFV gene mutation spectrum in patients with familial mediterranean fever.
explanation: This study discusses the gene mutations associated with FMF but does not describe subtypes of the disease.
- name: Type 2
description: A variant characterized by continuous subclinical inflammation, leading to amyloidosis without overt episodes.
evidence:
- reference: PMID:21358337
reference_title: "Familial Mediterranean fever--a review."
supports: SUPPORT
snippet: Familial Mediterranean fever type 2 is characterized by amyloidosis as the first clinical manifestation of familial Mediterranean fever in an otherwise asymptomatic individual.
explanation: The literature directly states that FMF type 2 is characterized by amyloidosis without prior overt inflammatory episodes, aligning with the given statement.
- reference: PMID:11053071
reference_title: "A survey of phenotype II in familial Mediterranean fever."
supports: PARTIAL
snippet: Phenotype II in familial Mediterranean fever (FMF) is the onset of amyloidosis before the onset of FMF with its typical attacks, or as an isolated finding in a member of an FMF family.
explanation: While this states Type 2 can involve amyloidosis without typical attacks, it does not directly mention continuous subclinical inflammation.
- reference: PMID:36161616
reference_title: "The effectiveness of anti-interleukin-1 therapy on subclinical inflammation parameters during the attack-free period in familial Mediterranean fever patients: A case-control study."
supports: PARTIAL
snippet: Anti IL-1 therapy is useful in suppressing attacks in FMF patients with colchicine resistance, however, it is not certain whether subclinical inflammation can sufficiently be inhibited with anti-IL-1 therapy in FMF patients with amyloidosis.
explanation: Reference to subclinical inflammation in amyloidosis supports part of the statement, but does not specifically mention Type 2 FMF.
- reference: PMID:37496356
reference_title: "Familial Mediterranean Fever-Related Amyloidosis in Turkey: A Need for a Familial Mediterranean Fever Registry."
supports: PARTIAL
snippet: Recent studies have shown that cases of amyloidosis in patients with familial Mediterranean fever are decreasing
explanation: Though it implies a relationship between FMF and amyloidosis, it does not clearly distinguish between subtypes or mention continuous subclinical inflammation.
prevalence:
- population: Mediterranean Populations
percentage: 0.1-0.2
evidence:
- reference: PMID:32608308
reference_title: "Characteristics of patients with familial Mediterranean fever in Denmark: a retrospective nationwide register-based cohort study."
supports: REFUTE
snippet: The predominant ethnicities were Turkish (41.8%), Lebanese (15.8%), Syrian (6.5%), South-West Asian (7.9%), and South-East Asian (3.0%).
explanation: The prevalence in Mediterranean populations, such as Turkish (41.8%) and Lebanese (15.8%), is much higher than 0.1-0.2%.
- reference: PMID:11053071
reference_title: "A survey of phenotype II in familial Mediterranean fever."
supports: NO_EVIDENCE
snippet: Phenotype II is uncommon among the relatives of patients with FMF and amyloidosis.
explanation: This study does not provide direct evidence on the overall prevalence of FMF in the Mediterranean populations.
- reference: PMID:3306755
reference_title: "Familial Mediterranean fever (recurrent hereditary polyserositis) in Arabs--a study of 175 patients and review of the literature."
supports: REFUTE
snippet: Recurrent hereditary polyserositis (RHP) or familial Mediterranean fever (FMF) is a chronic inherited illness of obscure aetiology... and predominantly affects Sephardic Jews, Arabs, Turks and Armenians.
explanation: The article suggests that FMF predominantly affects specific Mediterranean populations, implying a higher prevalence than 0.1-0.2% among these groups.
- reference: PMID:34363075
reference_title: "Prevalence of Familial Mediterranean Fever in Children with Cryptogenic Cirrhosis."
supports: NO_EVIDENCE
snippet: The aim of this study was to determine the prevalence of FMF in children with cryptogenic cirrhosis and it was found to be high, to add FMF among the etiological causes of cirrhosis
explanation: The study focused on children with cryptogenic cirrhosis and does not provide general prevalence data for Mediterranean populations.
progression:
- phase: Onset
age_range: Childhood-Adolescence
evidence:
- reference: PMID:31999206
reference_title: "Age of onset as an influencing factor for disease severity in children with familial Mediterranean fever."
supports: SUPPORT
snippet: Of 1687 patients, 761 had first FMF attack at </=3 years of age while 926 patients presented with their first manifestation of FMF at >3 years.
explanation: The study provides evidence that FMF onset can occur in childhood.
- reference: PMID:23194659
reference_title: "Familial Mediterranean Fever -- an increasingly important childhood disease in Sweden."
supports: SUPPORT
snippet: Median age at first symptoms was 4 years (range 3 month-37 years) and at diagnosis 10 years (range 2-44 years).
explanation: This reference supports the statement by indicating that the majority of FMF cases have an onset in childhood.
genetic:
- name: MEFV
association: Primary causal gene
notes: Encodes pyrin protein; gain-of-function mutations lower activation threshold for inflammasome assembly
evidence:
- reference: PMID:28154935
reference_title: "[Role of genetics in familial Mediterranean fever]."
supports: SUPPORT
snippet: Familial Mediterranean fever (FMF) is caused by mutations within the Mediterranean fever (MEFV) gene. These gain of function mutations lead to an increased activation of the inflammasome pyrin with a subsequent disproportional proinflammatory reaction.
explanation: Mutations in the MEFV gene result in increased activation of pyrin, causing excessive inflammation.
- reference: PMID:25307949
reference_title: "Immunological function of familial Mediterranean fever disease protein Pyrin."
supports: SUPPORT
snippet: Mutations in the MEFV gene are associated with the human autoinflammatory disease familial Mediterranean fever (FMF). Pyrin can interact with the inflammasome adaptor ASC and induce inflammatory caspase-1 activation in monocytic cells.
explanation: This article discusses the role of pyrin in inducing inflammatory responses, supporting the effect of MEFV gene mutations in causing excessive inflammation.
- reference: PMID:36889987
reference_title: "MEFV gene mutation spectrum in patients with familial mediterranean fever."
supports: PARTIAL
snippet: MEFV gene mutation spectrum in patients with familial mediterranean fever
explanation: This supports MEFV mutation involvement in FMF, but the quoted text alone does not establish the detailed gain-of-function/pyrin-threshold mechanism.
- reference: CGGV:assertion_d811d62e-7063-481a-922e-a3d1eb884971-2022-02-23T170000.000Z
reference_title: "MEFV / familial Mediterranean fever (Definitive)"
supports: SUPPORT
evidence_source: OTHER
snippet: "MEFV | HGNC:6998 | familial Mediterranean fever | MONDO:0018088 | SD | Definitive"
explanation: ClinGen classifies the MEFV-familial Mediterranean fever gene-disease relationship as definitive with semidominant inheritance.
- name: PKN1
association: Modifier gene
notes: Serine/threonine kinase that phosphorylates pyrin to maintain autoinhibition; acts downstream of RhoA
- name: PKN2
association: Modifier gene
notes: Partner kinase to PKN1; phosphorylates pyrin and enables 14-3-3 binding for inflammasome suppression
- name: RHOA
association: Upstream regulator
notes: Small GTPase whose inactivation relieves pyrin inhibition by reducing PKN activity
pathophysiology:
- name: MEFV Gene Mutation
description: Mutations in the MEFV gene lead to dysfunctional pyrin, causing excessive inflammation.
gene:
preferred_term: MEFV
evidence:
- reference: PMID:28154935
reference_title: "[Role of genetics in familial Mediterranean fever]."
supports: SUPPORT
snippet: Familial Mediterranean fever (FMF) is caused by mutations within the Mediterranean fever (MEFV) gene. These gain of function mutations lead to an increased activation of the inflammasome pyrin with a subsequent disproportional proinflammatory reaction.
explanation: Mutations in the MEFV gene result in increased activation of pyrin, causing excessive inflammation.
- reference: PMID:25307949
reference_title: "Immunological function of familial Mediterranean fever disease protein Pyrin."
supports: SUPPORT
snippet: Mutations in the MEFV gene are associated with the human autoinflammatory disease familial Mediterranean fever (FMF). Pyrin can interact with the inflammasome adaptor ASC and induce inflammatory caspase-1 activation in monocytic cells.
explanation: This article discusses the role of pyrin in inducing inflammatory responses, supporting the effect of MEFV gene mutations in causing excessive inflammation.
- reference: PMID:36889987
reference_title: "MEFV gene mutation spectrum in patients with familial mediterranean fever."
supports: PARTIAL
snippet: MEFV gene mutation spectrum in patients with familial mediterranean fever
explanation: Supports MEFV mutation relevance to FMF, but does not directly demonstrate the full mechanistic inflammation claim in this descriptor.
- name: RhoA-PKN Regulatory Pathway Dysregulation
description: Disruption of the RhoA-PKN1/2-14-3-3 checkpoint that normally restrains pyrin inflammasome activation, leading to lowered activation threshold.
cell_types:
- preferred_term: monocyte
term:
id: CL:0000576
label: monocyte
- preferred_term: neutrophil
term:
id: CL:0000775
label: neutrophil
biological_processes:
- preferred_term: interleukin-1 beta production
term:
id: GO:0032611
label: interleukin-1 beta production
notes: RhoA GTPase activates PKN1/2 kinases which phosphorylate pyrin, enabling 14-3-3 binding and autoinhibition; MEFV mutations or RhoA inactivation reduces this phosphorylation checkpoint
- name: Autoinflammatory Pathway Activation
description: Dysregulated inflammatory response due to pyrin dysfunction, leading to recurrent inflammatory episodes.
cell_types:
- preferred_term: monocyte
term:
id: CL:0000576
label: monocyte
- preferred_term: macrophage
term:
id: CL:0000235
label: macrophage
- preferred_term: neutrophil
term:
id: CL:0000775
label: neutrophil
biological_processes:
- preferred_term: pyroptotic inflammatory response
term:
id: GO:0070269
label: pyroptotic inflammatory response
- preferred_term: interleukin-1 beta production
term:
id: GO:0032611
label: interleukin-1 beta production
locations:
- preferred_term: peritoneum
term:
id: UBERON:0002358
label: peritoneum
- preferred_term: pleura
term:
id: UBERON:0000977
label: pleura
- preferred_term: synovial membrane of synovial joint
term:
id: UBERON:0002018
label: synovial membrane of synovial joint
downstream:
- target: Recurrent Fever and Serositis
description: MEFV mutations cause inflammasome activation and uncontrolled IL-1β production, resulting in recurrent attacks of fever and polyserositis.
evidence:
- reference: PMID:30938266
reference_title: "Familial Mediterranean fever: overview of pathogenesis, clinical features and management."
supports: SUPPORT
snippet: mutations in the MEFV gene encoding pyrin, which result in inflammasome activation and the uncontrolled production of IL-1β
explanation: This 2018 review explains that MEFV gene mutations cause pyrin dysfunction leading to inappropriate inflammasome activation and uncontrolled IL-1β production, which drives the characteristic recurrent fever episodes and inflammatory attacks.
pathways:
- preferred_term: IL-1β
term:
id: GO:0032611
label: interleukin-1 beta production
- preferred_term: inflammasome
evidence:
- reference: PMID:16344627
reference_title: "Familial Mediterranean fever and the other autoinflammatory syndromes: evaluation of the patient with recurrent fever."
supports: PARTIAL
snippet: The spectrum of reported genetic mutations and susceptible ethnicities for the hereditary periodic fever subset of the autoinflammatory diseases has continued to expand. At the same time, the pathogeneses of many of these diseases are now understood to involve different aspects of a common pathway, largely affecting inflammatory cascades related to IL-1 or tumor necrosis factor-alpha.
explanation: Supports shared IL-1/TNF inflammatory pathways in hereditary periodic fever syndromes, but only indirectly supports FMF-specific pathway details.
- reference: PMID:29148036
reference_title: "Function and mechanism of the pyrin inflammasome."
supports: SUPPORT
snippet: Pyrin, encoded by the MEFV gene, is an intracellular pattern recognition receptor that assembles inflammasome complexes in response to pathogen infections. Mutations in the MEFV gene have been linked to autoinflammatory diseases such as familial Mediterranean fever (FMF) or pyrin-associated autoinflammation with neutrophilic dermatosis (PAAND).
explanation: This reference describes the role of pyrin in inflammasome activation and its link to FMF, supporting the statement about dysregulated inflammatory responses and recurrent inflammatory episodes.
- reference: PMID:33026080
reference_title: "Familial Mediterranean fever: the molecular pathways from stress exposure to attacks."
supports: SUPPORT
snippet: FMF is an autoinflammatory disease characterized by recurrent attacks and increased IL-1 synthesis owing to activation of the pyrin inflammasome
explanation: This reference directly mentions recurrent attacks and increased IL-1 synthesis due to pyrin inflammasome activation, supporting the mechanisms described in the statement.
- reference: PMID:32601469
reference_title: "Ancient familial Mediterranean fever mutations in human pyrin and resistance to Yersinia pestis."
supports: SUPPORT
snippet: Familial Mediterranean fever (FMF) is an autoinflammatory disease caused by homozygous or compound heterozygous gain-of-function mutations in MEFV, which encodes pyrin, an inflammasome protein. Heterozygous carrier frequencies for multiple MEFV mutations are high in several Mediterranean populations, suggesting that they confer selective advantage.
explanation: This reference supports the genetic basis of FMF involving mutations in MEFV, which leads to the dysregulated inflammatory response observed in FMF.
- reference: PMID:29051974
reference_title: "Cardiac disease in familial Mediterranean fever."
supports: SUPPORT
snippet: Familial Mediterranean fever (FMF) is an autoinflammatory disease manifested by inflammatory attacks of peritonitis, pleuritis, pericarditis accompanied by fever and arthritis. Mutations of MEFV gene results in pyrin dysfunction, which causes uncontrolled interleukin-1 beta production and triggers the inflammatory attacks.
explanation: This reference supports the mechanism described in the statement, emphasizing pyrin dysfunction and the uncontrolled production of interleukin-1 beta.
- name: Gasdermin D-Mediated Pyroptosis
description: Caspase-1 cleaves gasdermin D to form membrane pores, enabling cytokine release and pyroptotic cell death, amplifying inflammation.
cell_types:
- preferred_term: neutrophil
term:
id: CL:0000775
label: neutrophil
- preferred_term: macrophage
term:
id: CL:0000235
label: macrophage
biological_processes:
- preferred_term: pyroptotic inflammatory response
term:
id: GO:0070269
label: pyroptotic inflammatory response
notes: Gasdermin D pores facilitate release of IL-1β, IL-18, and S100 alarmins (S100A8/A9/A12) that amplify the inflammatory response
phenotypes:
- category: Systemic
name: Recurrent Fever
frequency: VERY_FREQUENT
diagnostic: true
evidence:
- reference: PMID:21358337
reference_title: "Familial Mediterranean fever--a review."
supports: PARTIAL
snippet: Familial Mediterranean fever type 1 is characterized by recurrent short episodes of inflammation and serositis, including fever, peritonitis, synovitis, pleuritis, and, rarely, pericarditis.
explanation: The literature supports that recurrent fever is a common feature of Familial Mediterranean Fever type 1, but it does not fully support that FMF should be categorized solely under systemic phenotypes.
- reference: PMID:25832989
reference_title: "The myths we believed in familial Mediterranean fever: what have we learned in the past years?"
supports: PARTIAL
snippet: Familial Mediterranean fever...presents with recurrent and self-limited inflammatory attacks of fever and polyserositis along with high acute-phase reactants.
explanation: The literature supports that recurrent fever is a common diagnostic feature of FMF and systemically involves fever and inflammation, but it does not confirm all specified aspects of the statement.
- reference: PMID:36688581
reference_title: "Disease severity and genotype-phenotype correlation in adult patients with familial Mediterranean fever."
supports: PARTIAL
snippet: Higher Pras scores, earlier age of symptoms and diagnosis, more frequent arthritis and erysipelas-like erythema, and higher colchicine dose are closely associated with M694V homozygous familial Mediterranean fever patients. These patients also have mostly moderate and severe disease severity.
explanation: It supports the systemic nature and severity aspects but does not fully align with the complete statement's focus.
- reference: PMID:34606655
reference_title: "The analysis of genotype-phenotype correlation in familial Mediterranean fever."
supports: PARTIAL
snippet: Familial Mediterranean fever (FMF) is the most common monogenic autoinflammatory disease manifesting with phenotypic heterogeneity. It is a clinically diagnosed disease supported by Mediterranean fever gene mutation analysis.
explanation: While fever is a prominent symptom, FMF is known for phenotypic heterogeneity, indicating varied systemic manifestations.
phenotype_term:
preferred_term: Recurrent Fever
term:
id: HP:0001954
label: Recurrent fever
- category: Musculoskeletal
name: Arthritis
frequency: FREQUENT
notes: Transient, affecting large joints
evidence:
- reference: PMID:11411958
reference_title: "Arthritis in familial Mediterranean fever."
supports: SUPPORT
snippet: The arthritis was transient, monoarticular, nonerosive, and nondeforming in the majority of cases. Four patients (5.4%) had chronic arthritis, with one requiring total hip replacement. As in previous reports on arthritis of FMF, the majority of FMF patients studied in Lebanon had a transient monoarticular nonerosive and nondeforming type of arthritis affecting predominantly the large joints of the lower extremities.
explanation: This reference supports the statement that arthritis is a common phenotype in FMF, is transient, and affects large joints.
- reference: PMID:33124556
reference_title: "Erysipelas-like erythema in children with familial Mediterranean fever."
supports: SUPPORT
snippet: More patients had arthritis in the ELE group than in the other group (p=0.011). Arthritis occurred in the ankle (77.4%), knee (19.3%) and hip (3.2%) joints.
explanation: This reference confirms the presence of arthritis in FMF patients, especially in large joints, supporting the statement.
phenotype_term:
preferred_term: Arthritis
term:
id: HP:0001369
label: Arthritis
- category: Gastrointestinal
name: Peritonitis
frequency: VERY_FREQUENT
notes: Recurrent abdominal pain due to inflammation of the peritoneum
evidence:
- reference: PMID:36082189
reference_title: "Familial Mediterranean fever: a differential diagnosis for the surgical abdomen."
supports: PARTIAL
snippet: FMF is characterised by dysregulation of the inflammatory process in the body, presenting as recurrent episodes of serositis. Patients with FMF commonly present with episodes of fever, peritonitis, synovitis, pleuritis, arthritis, and occasionally pericarditis.
explanation: This reference supports that peritonitis, which involves abdominal pain due to inflammation of the peritoneum, is a phenotype of FMF. However, it does not explicitly indicate a high frequency of gastrointestinal phenotypes.
- reference: PMID:37723615
reference_title: "Evaluation of Gastrointestinal System Complaints and Comorbidities in Pediatric Familial Mediterranean Fever Patients."
supports: PARTIAL
snippet: Familial Mediterranean fever (FMF) is the most prevalent hereditary autoinflammatory disease among children. Abdominal pain and various gastrointestinal system (GIS) manifestations may arise directly from FMF or concomitantly with FMF.
explanation: This reference supports that gastrointestinal manifestations, including abdominal pain, are phenotypes of FMF. However, it does not specify the high frequency of peritonitis.
- reference: PMID:9562837
reference_title: "Familial Mediterranean fever: the genetics of inflammation."
supports: SUPPORT
snippet: When a patient complains of episodic fever accompanied by unexplained arthritis, peritonitis, pleurisy, or skin rash, this disorder should be considered.
explanation: This reference supports that peritonitis is a common phenotype of FMF, aligning well with the statement.
- reference: PMID:35737103
reference_title: "Familial Mediterranean fever may mimic acute appendicitis in children."
supports: SUPPORT
snippet: The key feature of familial Mediterranean fever is relapsing episodes of fever and serositis including peritonitis, pleurisy, or arthritis.
explanation: This reference clearly supports that peritonitis, involving abdominal pain due to inflammation of the peritoneum, is a key feature of FMF and occurs frequently.
- reference: PMID:31308342
reference_title: "Familial Mediterranean Fever with Small Bowel Stenosis."
supports: PARTIAL
snippet: Considering the history of recurrent abdominal pain, Familial Mediterranean Fever (FMF) was considered.
explanation: Supports recurrent abdominal pain as a clinical clue for FMF, but does not directly establish peritonitis frequency.
phenotype_term:
preferred_term: Peritonitis
term:
id: HP:0002586
label: Peritonitis
- category: Thoracic
name: Pleuritis
frequency: FREQUENT
notes: Recurrent chest pain due to inflammation of the pleura
phenotype_term:
preferred_term: Pleuritis
term:
id: HP:0002102
label: Pleuritis
evidence:
- reference: PMID:38204312
reference_title: "Chest pain in children with familial Mediterranean fever."
supports: PARTIAL
snippet: The most common signs and symptoms are fever, abdominal pain, chest pain, and arthritis.
explanation: Supports frequent chest pain in FMF, but does not directly specify pleuritis as the cause.
- reference: PMID:12092043
reference_title: "Thoracic and lung involvement in familial Mediterranean fever (FMF)."
supports: SUPPORT
snippet: Lung involvement in FMF is limited mainly to transient pleuritis during acute attacks.
explanation: The study specifies that pleuritis, which is inflammation of the pleura, is a frequent thoracic phenotype in FMF.
- reference: PMID:36385047
reference_title: "Transient and Recurrent Pulmonary Infiltrations Associated with Familial Mediterranean Fever."
supports: PARTIAL
snippet: Pericarditis, pleurisy and the response to colchicine indicated FMF.
explanation: This study identifies pleurisy, another term for pleuritis, as a characteristic symptom in FMF patients, supporting the statement.
- reference: PMID:36725780
reference_title: "Apical fibrosis was the most common incidental pulmonary finding in a familial Mediterranean fever cohort."
supports: PARTIAL
snippet: Pleuritis is the only known pulmonary involvement of FMF; however, as far as we know, thoracic involvements in pleural, parenchymal, bronchial, and vascular structures have not been evaluated yet.
explanation: While the study acknowledges pleuritis as a known pulmonary involvement in FMF, it does not provide evidence on its frequency being "FREQUENT".
- category: Cardiovascular
name: Pericarditis
frequency: OCCASIONAL
notes: Inflammation of the pericardium, less common than pleuritis or peritonitis
phenotype_term:
preferred_term: Pericarditis
term:
id: HP:0001701
label: Pericarditis
- category: Renal
name: Amyloidosis
frequency: OCCASIONAL
notes: Can lead to kidney failure if untreated
evidence:
- reference: PMID:12832747
reference_title: "Familial Mediterranean fever (FMF) and renal AA amyloidosis--phenotype-genotype correlation, treatment and prognosis."
supports: SUPPORT
snippet: Amyloidosis, causing renal failure, is one of the most severe complications of the disease.
explanation: The literature confirms that amyloidosis can lead to kidney failure in patients with Familial Mediterranean Fever (FMF), supporting the statement.
- reference: PMID:23548761
reference_title: "Renal involvement in AA amyloidosis: clinical outcomes and survival."
supports: SUPPORT
snippet: Familial Mediterranean Fever and tuberculosis were the most frequent causes of amyloidosis.
explanation: The statement is supported as FMF is listed as one of the frequent causes of renal amyloidosis.
- reference: PMID:21360109
reference_title: "Renal amyloidosis in children."
supports: SUPPORT
snippet: The most frequent cause [of renal amyloidosis in children] is now autoinflammatory diseases. Among this group of diseases, the most frequent one throughout the world is familial Mediterranean fever (FMF).
explanation: This confirms that FMF is a frequent cause of renal amyloidosis, thereby supporting the statement.
- reference: PMID:33052444
reference_title: "Menorrhagia due to uterine amyloidosis in familial Mediterranean fever: case-based review."
supports: SUPPORT
snippet: Amyloidosis [...] stands out as a major complication of familial Mediterranean fever (FMF). Splenic and renal involvement is more likely in FMF-associated systemic amyloidosis.
explanation: The literature confirms the renal involvement in FMF-associated amyloidosis, thus supporting the statement.
phenotype_term:
preferred_term: Amyloidosis
term:
id: HP:0011034
label: Amyloid deposition
- category: Integumentary
frequency: OCCASIONAL
name: Erysipelas-Like Erythema
notes: Recurrent erythematous skin lesions, usually on the lower legs
evidence:
- reference: PMID:21352275
reference_title: "Erysipelas-like erythema with familial Mediterranean fever."
supports: PARTIAL
snippet: Erysipelas-like erythema with familial Mediterranean fever.
explanation: Supports association between erysipelas-like erythema and FMF, but title-level text alone is limited evidence for phenotype frequency.
- reference: PMID:33124556
reference_title: "Erysipelas-like erythema in children with familial Mediterranean fever."
supports: SUPPORT
snippet: Erysipelas-like erythema (ELE) is a well-known pathognomonic skin lesion associated with familial Mediterranean fever (FMF).
explanation: The study describes ELE as a significant feature of FMF, supporting the statement that it is an occasional manifestation in the integumentary system.
- category: Musculoskeletal
frequency: OCCASIONAL
name: Myalgia
notes: Muscle pain, often in the legs, associated with fever episodes
phenotype_term:
preferred_term: Myalgia
term:
id: HP:0003326
label: Myalgia
evidence:
- reference: PMID:37309906
reference_title: "Exertional leg pain represents a severe disease phenotype in childhood familial Mediterranean fever."
supports: SUPPORT
snippet: Recurrent fever, serositis, and arthritis are common findings of the disease. In addition, musculoskeletal complaints such as exertional leg pain can be overlooked, although they are common and affect patients' quality of life.
explanation: The literature mentions musculoskeletal complaints, including exertional leg pain, as common in FMF, supporting the statement that myalgia is an occasional symptom.
- reference: PMID:32895731
reference_title: "Protracted febrile myalgia syndrome as the first manifestation of familial Mediterranean fever in children: case-based review."
supports: SUPPORT
snippet: Protracted febrile myalgia syndrome (PFMS) is one of the rare conditions characterized by long standing severe myalgia and fever in familial Mediterranean fever (FMF) patients.
explanation: This reference specifically mentions severe myalgia as a symptom in FMF patients, which supports the statement.
diagnosis:
- name: Genetic Testing
results: Identifies MEFV mutations
evidence:
- reference: PMID:29314663
reference_title: "MEFV gene testing may guide physicians for early diagnosis of familial Mediterranean fever."
supports: PARTIAL
snippet: Even though clinical assessment is accepted to be the most important factor in the diagnosis of FMF... MEFV gene assessment, unlike other diagnostic procedures, might support physicians in the early diagnosis of FMF.
explanation: The literature acknowledges the importance of genetic testing for MEFV mutations but emphasizes that clinical evaluation remains crucial for diagnosis overall.
- reference: PMID:25649364
reference_title: "Familial Mediterranean Fever."
supports: PARTIAL
snippet: Genetic mutation of the disease is on MEFV gene located on short arm of Chromosome 16. The disease is diagnosed based on clinical evaluation.
explanation: Supports MEFV genetic basis, but also states diagnosis is primarily clinical, so this is only partial support for the testing claim.
- reference: PMID:12168253
reference_title: "[Genetic diagnosis of periodic diseases (familial mediterranean fever or FMF)]."
supports: SUPPORT
snippet: This strategy allows definitive confirmation of periodic disease if one mutation is detected on each of the two chromosomes...
explanation: This reference directly supports the use of genetic testing to identify MEFV mutations for diagnosing familial Mediterranean fever.
- reference: PMID:33037005
reference_title: "Fast diagnostic test for familial Mediterranean fever based on a kinase inhibitor."
supports: SUPPORT
snippet: Its diagnosis relies on a set of clinical criteria and a genetic confirmation on identification of biallelic pathogenic MEFV variants.
explanation: The reference confirms that genetic testing for MEFV mutations is a key part of diagnosing familial Mediterranean fever.
- name: Inflammatory Markers
presence: Elevated
markers: CRP, ESR, SAA
evidence:
- reference: PMID:31524848
reference_title: "The Value of Serum Amyloid A Levels in Familial Mediterranean Fever to Identify Occult Inflammation During Asymptomatic Periods."
supports: SUPPORT
snippet: Median values of acute phase reactants during FMF attacks were 433.5 mg/L ... for serum amyloid A (SAA), 56.7 mg/L ... for C-reactive protein (CRP), and 37.5 mm/h ... for erythrocyte sedimentation rate (ESR).
explanation: The study shows that SAA, CRP, and ESR are elevated during FMF attacks.
- reference: PMID:23794006
reference_title: "As a new inflammatory marker for familial Mediterranean fever: neutrophil-to-lymphocyte ratio."
supports: SUPPORT
snippet: We found that the NLR values of the patients were significantly higher than those of the control group, and C-reactive protein values were correlated with NLR.
explanation: CRP is confirmed as an elevated marker in FMF patients in this study as well.
environmental:
- name: Physical Stress
effect: May trigger episodes
evidence:
- reference: PMID:22234484
reference_title: "Triggers for attacks in familial Mediterranean fever: application of the case-crossover design."
supports: PARTIAL
snippet: Multiple stressful life events predicted FMF attacks 2 days following the event. ... Physical exertion and high-fat diet did not increase the likelihood of FMF attacks.
explanation: The study found that emotional stress could trigger FMF attacks, but physical stress did not show a significant effect. Therefore, while stress in general may trigger episodes, physical stress specifically does not.
- name: Emotional Stress
effect: Potential trigger for flare-ups
evidence:
- reference: PMID:22234484
reference_title: "Triggers for attacks in familial Mediterranean fever: application of the case-crossover design."
supports: SUPPORT
snippet: Multiple stressful life events predicted FMF attacks 2 days following the event. After adjustment for treatment, an additional stressful event was associated with an estimated 70% increase in the odds of having an FMF attack on the second day.
explanation: The study indicates a clear association between emotional stress and the triggering of FMF attacks, supporting the statement.
- reference: PMID:33026080
reference_title: "Familial Mediterranean fever: the molecular pathways from stress exposure to attacks."
supports: SUPPORT
snippet: The emergence of FMF attacks after emotional stress and the induction of attacks with metaraminol in previous decades suggested that stress-induced sympathoadrenal system activation might play a role in inflammasome activation and triggering attacks.
explanation: The literature provides evidence that emotional stress can trigger FMF attacks through the activation of the inflammasome pathway.
exposure_term:
preferred_term: Emotional stress exposure
treatments:
- name: Colchicine
description: First-line treatment to prevent and reduce the frequency of attacks and the risk of amyloidosis.
evidence:
- reference: PMID:19797919
reference_title: "Prevention of amyloidosis in familial Mediterranean fever with colchicine: a case-control study in Armenia."
supports: SUPPORT
snippet: The study demonstrated that colchicine treatment is effective in preventing amyloidosis among Armenian patients with FMF and that earlier initiation and continuous therapy at an adequate dose of 1.2-1.8 mg/day may be associated with a decreased amyloidosis risk among Armenian patients with FMF.
explanation: The study directly supports the statement that colchicine is a first-line treatment for preventing amyloidosis, a common complication of FMF.
- reference: PMID:25649364
reference_title: "Familial Mediterranean Fever."
supports: SUPPORT
snippet: The only agent that decreases the development of amyloidosis and the frequency and severity of the episodes is colchicine, which has been used for about 40 years.
explanation: This reference clearly supports the claim that colchicine reduces the frequency of attacks and prevents amyloidosis, affirming its role as a first-line treatment.
- reference: PMID:25791871
reference_title: "Interventions for reducing inflammation in familial Mediterranean fever."
supports: SUPPORT
snippet: Early studies reported colchicine as a potential drug for preventing attacks of familial Mediterranean fever.
explanation: This indicates that colchicine is considered effective for preventing FMF attacks, supporting its position as a first-line treatment.
- reference: PMID:17242135
reference_title: "Colchicine use in children and adolescents with familial Mediterranean fever: literature review and consensus statement."
supports: SUPPORT
snippet: The daily application of colchicine is the standard therapy for prophylaxis of attacks and amyloid deposition in familial Mediterranean fever.
explanation: This statement corroborates that colchicine is the standard, or first-line, therapy for preventing FMF attacks and amyloidosis.
- reference: PMID:15720245
reference_title: "Pharmacological and clinical basis of treatment of Familial Mediterranean Fever (FMF) with colchicine or analogues: an update."
supports: SUPPORT
snippet: Since 1972 colchicine has become the drug of choice for prophylaxis against FMF attacks and amyloidosis FMF-associated.
explanation: This reference supports the idea that colchicine is the primary treatment for preventing FMF attacks and associated amyloidosis.
treatment_term:
preferred_term: pharmacotherapy
term:
id: MAXO:0000058
label: pharmacotherapy
therapeutic_agent:
- preferred_term: colchicine
term:
id: CHEBI:23359
label: colchicine
- name: Anti-IL-1 Therapy
description: Used in colchicine-resistant cases to control inflammation (e.g., anakinra, canakinumab).
evidence:
- reference: PMID:28362189
reference_title: "Canakinumab for the treatment of familial Mediterranean fever."
supports: SUPPORT
snippet: The accumulating data indicates that anti IL-1 drugs are effective in treating colchicine resistant FMF cases and improving their quality of life.
explanation: The reference supports the use of anti-IL-1 therapy for treating colchicine-resistant FMF cases.
- reference: PMID:30338514
reference_title: "Interventions for reducing inflammation in familial Mediterranean fever."
supports: PARTIAL
snippet: For those people who are colchicine-resistant or intolerant, drugs such as rilonacept, anakinra, canakinumab, etanercept, infliximab, thalidomide and interferon-alpha might be beneficial.
explanation: Provides mixed, tentative treatment options; this is partial support for anti-IL-1 use in colchicine-resistant FMF.
- reference: PMID:36161616
reference_title: "The effectiveness of anti-interleukin-1 therapy on subclinical inflammation parameters during the attack-free period in familial Mediterranean fever patients: A case-control study."
supports: SUPPORT
snippet: Anti IL-1 therapy is useful in suppressing attacks in FMF patients with colchicine resistance.
explanation: The study supports the effectiveness of anti-IL-1 therapy in managing inflammation in colchicine-resistant FMF patients.
- reference: PMID:27860460
reference_title: "Anakinra for Colchicine-Resistant Familial Mediterranean Fever: A Randomized, Double-Blind, Placebo-Controlled Trial."
supports: SUPPORT
snippet: In this randomized controlled trial, anakinra appears to be an effective and safe treatment for colchicine-resistant FMF.
explanation: The reference provides evidence from a randomized controlled trial supporting the effectiveness of anakinra, an anti-IL-1 therapy, in colchicine-resistant FMF patients.
treatment_term:
preferred_term: pharmacotherapy
term:
id: MAXO:0000058
label: pharmacotherapy
- name: NSAIDs
description: Used for symptom relief during acute attacks
evidence:
- reference: PMID:37752496
reference_title: "Treat-to-target strategies for the management of familial Mediterranean Fever in children."
supports: REFUTE
snippet: 'These provide the basis for stratifying patients into the following treatment paths: continue colchicine, persisting attacks / inflammation, colchicine intolerance, persisting arthritis, colchicine reduction and adjustment/reduction of biologics.'
explanation: The literature does not mention NSAIDs as a treatment path for symptom relief during acute attacks of Familial Mediterranean Fever. The focus is on colchicine and biological therapy.
- reference: PMID:36945975
reference_title: "Factors affecting patient-acceptable symptom states and treatment decision in familial Mediterranean fever."
supports: NO_EVIDENCE
snippet: Mean age of the overall group was 38.2 +/- 11.7 years (62.4% female, 37.6% male). Two hundred and twenty-seven patients were treated with colchicine, 97 patients with colchicine plus Interleukin-1 (IL-1) antagonist, and 22 only with IL-1 antagonist (67.1%, 26.3%, 6.64% in order).
explanation: There is no mention of NSAIDs being used for symptom relief during acute attacks in FMF patients. The treatments focus on colchicine and IL-1 antagonist.
treatment_term:
preferred_term: NSAID therapy
term:
id: MAXO:0000221
label: NSAID therapy
- name: Lifestyle Modifications
description: Avoiding known triggers such as stress and infections where possible
evidence:
- reference: PMID:38488998
reference_title: "Factors triggering familial mediterranean fever attacks, do they really exist?"
supports: PARTIAL
snippet: Patients can significantly decrease the number of familial Mediterranean fever attacks they experience by managing psychological stress and avoiding physical factors such as cold exposure and fatigue.
explanation: The literature supports the management of psychological stress and avoiding physical factors as triggers but does not explicitly mention infections.
- reference: PMID:26324575
reference_title: "Familial Mediterranean Fever: An Unusual Case Presentation."
supports: PARTIAL
snippet: Triggers of this illness include many things, such as cold or stress.
explanation: The literature mentions stress as a trigger but does not provide exhaustive confirmation about infections as triggers or other preventive lifestyle modifications.
treatment_term:
preferred_term: dietary intervention
term:
id: MAXO:0000088
label: dietary intervention
disease_term:
preferred_term: familial Mediterranean fever
term:
id: MONDO:0018088
label: familial Mediterranean fever
classifications:
harrisons_chapter:
- classification_value: immune system disorder
- classification_value: hereditary disease
Familial Mediterranean fever is a prototypic inflammasomopathy caused by gain‑of‑function variants in MEFV encoding pyrin, a cytosolic inflammasome sensor in monocytes and neutrophils. Pathogenesis centers on dysregulated pyrin inflammasome assembly with downstream caspase‑1 activation, maturation and release of IL‑1β and IL‑18, gasdermin D–mediated pore formation and pyroptosis, and amplification by neutrophil/monocyte alarmins (S100 proteins). At baseline, pyrin is restrained by RhoA–PKN1/2–14‑3‑3 phosphorylation‑dependent autoinhibition; genetic variants and specific triggers lower the activation threshold and favor spontaneous or easily triggered inflammasome assembly (park2016pyrininflammasomeactivation pages 1-10, bella2024thepyrininflammasome pages 8-10, bella2024thepyrininflammasome pages 6-7, bella2024thepyrininflammasome pages 1-2).
Direct quote supporting the core mechanism: “RhoA activated the serine-threonine kinases PKN1 and PKN2 that bind and phosphorylate pyrin. Phosphorylated pyrin bound to 14-3-3 proteins… [and] blocked the pyrin inflammasome.” (Nature Immunology, 2016; URL: https://doi.org/10.1038/ni.3457; published Jun 2016) (park2016pyrininflammasomeactivation pages 1-10).
Recent reviews and experimental work in 2023–2024 refine these mechanisms by implicating PP2A activity in positively regulating pyrin via dephosphorylation, highlighting cytoskeletal control and gasdermin D as essential executioners, and identifying endogenous steroid catabolites and alarmins (S100A8/A9/A12) as important amplifiers and biomarkers in pyrin‑mediated inflammation (Frontiers in Immunology 2024, https://doi.org/10.3389/fimmu.2023.1341680; mBio 2023, https://doi.org/10.1128/mbio.02066-23; Frontiers in Pediatrics 2024, https://doi.org/10.3389/fped.2024.1421353) (bella2024thepyrininflammasome pages 8-10, bella2024thepyrininflammasome pages 6-7, bella2024thepyrininflammasome pages 5-6, chaaban2024anarrativereview pages 19-20, bella2024thepyrininflammasome pages 1-2).
| Entity | Type / Ontology | Identifier | Role in FMF pathophysiology (one sentence) | Evidence (year & DOI URL) (context ID) | Notes |
|---|---|---|---|---|---|
| MEFV / pyrin | Gene / inflammasome sensor (HGNC:MEFV) | HGNC:MEFV | Cytosolic inflammasome sensor whose gain-of-function variants lower activation threshold and drive caspase-1–dependent IL-1β/IL-18 release. | 2016 10.1038/ni.3457; 2024 10.3389/fimmu.2023.1341680 (park2016pyrininflammasomeactivation pages 1-10, bella2024thepyrininflammasome pages 5-6) | Central causal gene in FMF; exon 10 (B30.2) variants frequent. |
| PKN1 | Ser/Thr kinase (GO:protein kinase activity) | PKN1 | Phosphorylates pyrin (S208/S242) downstream of RhoA to enforce pyrin autoinhibition. | 2016 10.1038/ni.3457 (park2016pyrininflammasomeactivation pages 1-10) | Works with PKN2 to enable 14-3-3 binding. |
| PKN2 | Ser/Thr kinase (GO:protein kinase activity) | PKN2 | Partner kinase to PKN1 that phosphorylates pyrin and maintains 14-3-3–mediated inhibition. | 2016 10.1038/ni.3457 (park2016pyrininflammasomeactivation pages 1-10) | Reductions in PKN2 binding seen with pathogenic MEFV variants. |
| 14-3-3 (YWHA family) | Chaperone family (YWHA genes) | YWHA* | Binds phosphorylated pyrin to prevent inflammasome assembly. | 2016 10.1038/ni.3457 (park2016pyrininflammasomeactivation pages 1-10) | Loss of 14-3-3 binding occurs with reduced pyrin phosphorylation. |
| PP2A (PPP2CA/PPP2CB) | Ser/Thr phosphatase (PPP family) | PPP2CA / PPP2CB | Phosphatase activity implicated in dephosphorylating pyrin to permit inflammasome activation. | 2023 10.1128/mbio.02066-23; 2024 10.3389/fimmu.2023.1341680 (bella2024thepyrininflammasome pages 8-10, bella2024thepyrininflammasome pages 5-6) | PP2A involvement described as counterbalancing PKN-mediated phosphorylation. |
| RhoA | Small GTPase (HGNC:RHOA) | RHOA | Upstream GTPase whose inactivation (by toxins or prenylation defects) reduces PKN activity and relieves pyrin inhibition. | 2016 10.1038/ni.3457; 2024 10.3389/fimmu.2023.1341680 (park2016pyrininflammasomeactivation pages 1-10, bella2024thepyrininflammasome pages 5-6) | Targets of bacterial effectors converge here. |
| ASC (PYCARD) | Inflammasome adaptor (HGNC:PYCARD) | PYCARD | Adaptor recruited by pyrin PYD to assemble ASC specks and recruit pro–caspase-1. | 2024 10.3389/fimmu.2023.1341680 (bella2024thepyrininflammasome pages 5-6) | Required for caspase-1 activation and downstream signaling. |
| CASP1 (caspase-1) | Effector protease (CASP family) | CASP1 | Cleaves pro–IL-1β and pro–IL-18 to active forms and cleaves GSDMD to trigger pyroptosis. | 2016 10.1038/ni.3457; 2024 10.3389/fimmu.2023.1341680 (park2016pyrininflammasomeactivation pages 1-10, bella2024thepyrininflammasome pages 5-6) | Central executor of canonical inflammasome responses. |
| GSDMD (gasdermin D) | Pore-forming effector (GSDM family) | GSDMD | N-terminal fragment forms membrane pores enabling cytokine release and pyroptotic cell death. | 2024 10.3389/fimmu.2023.1341680; 2024 10.3389/fped.2024.1421353 (bella2024thepyrininflammasome pages 8-10, chaaban2024anarrativereview pages 19-20) | GSDMD pores also permit release of alarmins (S100 proteins). |
| IL1B (IL‑1β) | Proinflammatory cytokine (HGNC:IL1B) | IL1B | Principal downstream cytokine driving fever, serositis and systemic inflammation in FMF. | 2016 10.1038/ni.3457; 2024 10.3389/fped.2024.1421353 (park2016pyrininflammasomeactivation pages 1-10, chaaban2024anarrativereview pages 19-20) | Target of effective biologic therapies in colchicine-resistant disease. |
| IL18 | Proinflammatory cytokine (HGNC:IL18) | IL18 | Co-released with IL-1β from pyrin inflammasome activation and contributes to inflammation. | 2016 10.1038/ni.3457; 2024 10.3389/fped.2024.1421353 (park2016pyrininflammasomeactivation pages 1-10, chaaban2024anarrativereview pages 19-20) | Elevated in FMF flares and some steady‑state measurements. |
| S100A8/A9/A12 (alarmins) | Damage-associated proteins (CHEBI/S100 family) | S100A8 / S100A9 / S100A12 | Neutrophil/monocyte alarmins released during pyroptosis that amplify inflammation and serve as biomarkers. | 2024 10.3389/fimmu.2023.1341680; 2024 10.3389/fped.2024.1421353 (bella2024thepyrininflammasome pages 8-10, chaaban2024anarrativereview pages 19-20) | S100A levels correlate with disease activity and may be GSDMD-dependent. |
| PSTPIP1 (CD2BP1) | Cytoskeletal adaptor (HGNC:PSTPIP1) | PSTPIP1 | Interacts with pyrin to modulate oligomerization and inflammasome assembly; variants linked to hyperinflammation. | 2024 10.3389/fimmu.2023.1341680 (bella2024thepyrininflammasome pages 5-6) | Mutations can produce overlapping autoinflammatory phenotypes. |
| Colchicine | Drug / microtubule inhibitor (CHEBI) | CHEBI:Colchicine | First‑line therapy that disrupts microtubules and reduces pyrin inflammasome activation and attacks. | 2024 10.15167/bustaffa-marta_phd2024-05-28; 2024 10.3389/fimmu.2023.1341680 (bustaffa2024theeurofeverfmf pages 76-79, bella2024thepyrininflammasome pages 5-6) | Effective for attack prevention and amyloidosis prophylaxis; some genotypes show reduced response. |
| Anakinra | IL‑1 receptor antagonist (drug) | ANAKINRA | Blocks IL‑1 signaling to rapidly control pyrin-mediated systemic inflammation in colchicine‑resistant cases. | 2024 10.3389/fped.2024.1421353; 2024 10.15167/bustaffa-marta_phd2024-05-28 (chaaban2024anarrativereview pages 19-20, bustaffa2024theeurofeverfmf pages 76-79) | Used off‑label/approved in refractory FMF; rapid onset. |
| Canakinumab | Anti–IL‑1β monoclonal antibody (drug) | CANAKINUMAB | Neutralizes IL‑1β to reduce flares in patients unresponsive or intolerant to colchicine. | 2024 10.3389/fped.2024.1421353; 2024 10.15167/bustaffa-marta_phd2024-05-28 (chaaban2024anarrativereview pages 19-20, bustaffa2024theeurofeverfmf pages 76-79) | Long‑acting IL‑1β blockade option. |
| Rilonacept | IL‑1 trap (biologic) | RILONACEPT | Binds IL‑1α/β preventing receptor engagement and decreasing FMF inflammation in resistant cases. | 2024 10.3389/fped.2024.1421353 (chaaban2024anarrativereview pages 19-20) | Alternative IL‑1–directed therapy. |
| GGPP (geranylgeranyl pyrophosphate) | Metabolite (CHEBI) | GGPP | Prenylation substrate whose deficiency (e.g., in HIDS) leads to RhoA inactivation and pyrin activation; exogenous GGPP can suppress response. | 2016 10.1038/ni.3457 (park2016pyrininflammasomeactivation pages 1-10) | Links metabolic/prenylation defects to pyrin activation. |
| Pregnanolone & etiocholanolone | Steroid catabolites (CHEBI) | Pregnanolone / Etiocholanolone | Endogenous catabolites that can directly activate pyrin (B30.2-dependent) independent of RhoA. | 2024 10.3389/fimmu.2023.1341680 (bella2024thepyrininflammasome pages 6-7) | May explain non‑infectious triggers of flares. |
| Yersinia effectors (YopE/YopT/YopM) | Bacterial virulence proteins | YopE / YopT / YopM | Pathogen effectors that inactivate RhoA (YopE/T) or modulate PKN/14‑3‑3 (YopM) to trigger or evade pyrin responses. | 2016 10.1038/ni.3457; 2020 10.1038/s41590-020-0705-6 (park2016pyrininflammasomeactivation pages 1-10) | Historical selection of MEFV variants linked to resistance to Y. pestis (see Park et al.). |
| C. difficile TcdB | Bacterial toxin | TcdB | Toxin that inactivates Rho GTPases and can trigger pyrin inflammasome activation. | 2024 10.3389/fimmu.2023.1341680 (bella2024thepyrininflammasome pages 6-7) | Example of non‑Yersinia effector causing RhoA perturbation. |
| Neutrophils | Immune cell (CL:0000775) | CL:0000775 | Major effector cells in FMF attacks that release IL‑1, S100 alarmins, form NETs and undergo pyroptosis contributing to tissue inflammation. | 2024 10.3389/fimmu.2023.1341680; 2024 10.3389/fped.2024.1421353 (bella2024thepyrininflammasome pages 8-10, chaaban2024anarrativereview pages 19-20) | Abundant in serosal and synovial inflammatory infiltrates during attacks. |
| Monocytes / macrophages | Immune cell (CL:0000235) | CL:0000235 | Primary cells where pyrin inflammasome assembles, producing IL‑1β/IL‑18 and driving systemic symptoms. | 2016 10.1038/ni.3457; 2024 10.3389/fimmu.2023.1341680 (park2016pyrininflammasomeactivation pages 1-10, bella2024thepyrininflammasome pages 5-6) | Source of circulating IL‑1 and priming signals. |
| Peritoneum | Tissue (UBERON) | UBERON:0002106 | Frequent anatomical site of FMF serositis causing abdominal pain during attacks. | 2024 10.15167/bustaffa-marta_phd2024-05-28 (bustaffa2024theeurofeverfmf pages 76-79) | Clinically implicated in peritonitis episodes. |
| Pleura | Tissue (UBERON) | UBERON:0001004 | Site of pleuritic pain/serositis in FMF attacks. | 2024 10.15167/bustaffa-marta_phd2024-05-28 (bustaffa2024theeurofeverfmf pages 76-79) | Pleuritis is a common attack manifestation. |
| Synovium | Tissue (UBERON) | UBERON:0002381 | Joint tissue involved in FMF arthritis during inflammatory episodes. | 2024 10.15167/bustaffa-marta_phd2024-05-28 (bustaffa2024theeurofeverfmf pages 76-79) | Acute mono/oligoarthritis is typical. |
| Kidney (AA amyloidosis) | Organ / pathology (UBERON / HP) | UBERON:0002113 / HP:0001973 | Major long-term complication from chronic IL‑1–driven inflammation leading to AA amyloid deposition and renal impairment. | 2024 10.15167/bustaffa-marta_phd2024-05-28; 2024 10.3389/fimmu.2023.1341680 (bustaffa2024theeurofeverfmf pages 76-79, bella2024thepyrininflammasome pages 5-6) | Risk reduced by effective colchicine and IL‑1 suppression. |
Table: Compact ontology‑grounded table summarizing key genes, proteins, cells, tissues, triggers and therapies in FMF with evidence links to the gathered literature (pqac context IDs and DOIs).
Downstream execution: Caspase‑1 cleaves pro‑IL‑1β and pro‑IL‑18, and gasdermin D (GSDMD) to form pores causing cytokine release and pyroptosis; GSDMD pores facilitate release of S100A8/A9 alarmins that amplify inflammation (Frontiers in Immunology 2024, https://doi.org/10.3389/fimmu.2023.1341680; Frontiers in Pediatrics 2024, https://doi.org/10.3389/fped.2024.1421353) (bella2024thepyrininflammasome pages 8-10, chaaban2024anarrativereview pages 19-20, bella2024thepyrininflammasome pages 1-2).
Dysregulated molecular pathways:
Phosphorylation/dephosphorylation balance (PKN1/2 vs. PP2A) as a rheostat of pyrin activity (park2016pyrininflammasomeactivation pages 1-10, bella2024thepyrininflammasome pages 8-10).
Affected cellular processes:
Evolutionary context: MEFV variants show signals of positive selection in Mediterranean populations, with functional data linking mutant pyrin to resistance against Yersinia pestis via preserved IL‑1β responses despite YopM-mediated suppression (Nature Immunology 2020, https://doi.org/10.1038/s41590-020-0705-6; published Jun 2020) (park2016pyrininflammasomeactivation pages 1-10).
Expert synthesis from a 2024 pediatric rheumatology perspective: pyrin inflammasome activation is “strictly dependent on homeostasis‑altering molecular processes,” with RhoA–PKN–14‑3‑3 regulation, cytoskeletal cues, GSDMD pores, and S100 alarmins forming an integrated axis of dysregulated innate immunity in FMF (Frontiers in Immunology 2024, published Jan 2024; URL: https://doi.org/10.3389/fimmu.2023.1341680) (bella2024thepyrininflammasome pages 1-2).
FMF pathophysiology is driven by a failure of the RhoA–PKN1/2–14‑3‑3 checkpoint that restrains pyrin, with MEFV variants and specific triggers enabling PP2A‑assisted dephosphorylation and assembly of the pyrin inflammasome. Caspase‑1–dependent IL‑1β/IL‑18 release and GSDMD‑mediated pyroptosis, together with S100 alarmin amplification, explain the febrile serositis, arthritis, and risk of AA amyloidosis. 2023–2024 work highlights PP2A as a positive regulator and integrates cytoskeletal control, endogenous steroid catabolites, and alarmin biology into an updated model. Clinically, colchicine remains foundational, while IL‑1–targeted biologics are effective for colchicine‑resistant disease (park2016pyrininflammasomeactivation pages 1-10, bella2024thepyrininflammasome pages 8-10, bella2024thepyrininflammasome pages 6-7, bella2024thepyrininflammasome pages 5-6, chaaban2024anarrativereview pages 19-20, chaaban2024anarrativereview pages 3-4, bustaffa2024theeurofeverfmf pages 76-79, bella2024thepyrininflammasome pages 1-2).
References
(park2016pyrininflammasomeactivation pages 1-10): Yong Hwan Park, Geryl Wood, Daniel L Kastner, and Jae Jin Chae. Pyrin inflammasome activation and rhoa signaling in the autoinflammatory diseases fmf and hids. Nature Immunology, 17:914-921, Jun 2016. URL: https://doi.org/10.1038/ni.3457, doi:10.1038/ni.3457. This article has 646 citations and is from a highest quality peer-reviewed journal.
(bella2024thepyrininflammasome pages 8-10): Saverio La Bella, Armando Di Ludovico, Giulia Di Donato, Ozge Basaran, Seza Ozen, Marco Gattorno, Francesco Chiarelli, and Luciana Breda. The pyrin inflammasome, a leading actor in pediatric autoinflammatory diseases. Frontiers in Immunology, Jan 2024. URL: https://doi.org/10.3389/fimmu.2023.1341680, doi:10.3389/fimmu.2023.1341680. This article has 23 citations and is from a peer-reviewed journal.
(bella2024thepyrininflammasome pages 6-7): Saverio La Bella, Armando Di Ludovico, Giulia Di Donato, Ozge Basaran, Seza Ozen, Marco Gattorno, Francesco Chiarelli, and Luciana Breda. The pyrin inflammasome, a leading actor in pediatric autoinflammatory diseases. Frontiers in Immunology, Jan 2024. URL: https://doi.org/10.3389/fimmu.2023.1341680, doi:10.3389/fimmu.2023.1341680. This article has 23 citations and is from a peer-reviewed journal.
(bella2024thepyrininflammasome pages 1-2): Saverio La Bella, Armando Di Ludovico, Giulia Di Donato, Ozge Basaran, Seza Ozen, Marco Gattorno, Francesco Chiarelli, and Luciana Breda. The pyrin inflammasome, a leading actor in pediatric autoinflammatory diseases. Frontiers in Immunology, Jan 2024. URL: https://doi.org/10.3389/fimmu.2023.1341680, doi:10.3389/fimmu.2023.1341680. This article has 23 citations and is from a peer-reviewed journal.
(bella2024thepyrininflammasome pages 5-6): Saverio La Bella, Armando Di Ludovico, Giulia Di Donato, Ozge Basaran, Seza Ozen, Marco Gattorno, Francesco Chiarelli, and Luciana Breda. The pyrin inflammasome, a leading actor in pediatric autoinflammatory diseases. Frontiers in Immunology, Jan 2024. URL: https://doi.org/10.3389/fimmu.2023.1341680, doi:10.3389/fimmu.2023.1341680. This article has 23 citations and is from a peer-reviewed journal.
(chaaban2024anarrativereview pages 19-20): Ahlam Chaaban, Hasan Yassine, Razane Hammoud, Ruba Kanaan, Louna Karam, and José-Noel Ibrahim. A narrative review on the role of cytokines in the pathogenesis and treatment of familial mediterranean fever: an emphasis on pediatric cases. Frontiers in Pediatrics, Jul 2024. URL: https://doi.org/10.3389/fped.2024.1421353, doi:10.3389/fped.2024.1421353. This article has 10 citations and is from a poor quality or predatory journal.
(bustaffa2024theeurofeverfmf pages 76-79): MARTA BUSTAFFA. The eurofever fmf longitudinal cohort: first update on the longitudinal data. Other, May 2024. URL: https://doi.org/10.15167/bustaffa-marta_phd2024-05-28, doi:10.15167/bustaffa-marta_phd2024-05-28. This article has 0 citations.
(chaaban2024anarrativereview pages 3-4): Ahlam Chaaban, Hasan Yassine, Razane Hammoud, Ruba Kanaan, Louna Karam, and José-Noel Ibrahim. A narrative review on the role of cytokines in the pathogenesis and treatment of familial mediterranean fever: an emphasis on pediatric cases. Frontiers in Pediatrics, Jul 2024. URL: https://doi.org/10.3389/fped.2024.1421353, doi:10.3389/fped.2024.1421353. This article has 10 citations and is from a poor quality or predatory journal.