The Autoinflammatory Diseases

Under the term of autoinflammatory diseases are gathered a number of inherited disorders secondary to mutations of genes coding for proteins that play a pivotal role in the regulation of the inflammatory response. Most of these disorders have generally an early onset, ranging from the first hours to the first decade of life. The clinical spectrum of these disorders is extremely variable (Table I).

1) Periodic Fevers
Familial Mediterranean Fever (FMF), Mevalonate-kinase deficiency (MKD), and Tumour necrosis factor (TNF) Receptor-Associated Periodic Syndrome  (TRAPS) are the three monogenic disorders gathered under the term of Periodic fevers.These diseases are characterized by recurrent flares of systemic inflammation presenting as sudden fever episodes associated with a dramatic elevation of acute phase reactants and with a number of clinical manifestations, such as rash, serositis (peritonitis, pleuritis), lymphadenopathy, arthritis. Disease flares are usually separated by symptom-free intervals of variable duration, characterized by a complete well-being, normal growth and complete normalization of acute phase reactants.

2) NLRPs-related Autoinflammatory diseases
In other disorders, systemic inflammation is dominated by a characteristic urticarial rash associated with a number of other clinical manifestations. Familiar Cold Autoinflammatory Syndrome (FCAS), Muckle-Wells Syndrome (MWS) and Chronic Infantile Neurological Cutaneous and Articular Syndrome (CINCA) represent the clinical spectrum associated to different mutations of a gene named NLRP3 (or CIAS1, or NALP3 cold induced autoinflammatory syndrome 1) coding for a protein called Cryopyrin. These three disorders are also gathered under the term of Cryopyrinopathies or cryopyrin-related periodic syndromes (CAPS). Mutations of an other member of the NLRP family, the NLRP12 gene, have been recently associated with a new autoinflammatory disease.

3) Granulomatous disorders
Other diseases are characterized by typical granulomatous formations. Blau’s syndrome is characterized by noncaseating granulomatous inflammation affecting the joint, skin, and uveal tract  and is associated with mutations of the CARD15 (or NOD2) gene.

4) Pyogenic disorders.
A further group of diseases are dominated by the presence of sterile pyogen abscesses affecting skin, joints and bones  This include the Pyogenic Sterile Arthritis, Pyoderma Gangrenosum and Acne (PAPA) syndrome secondary to  mutations of the CD2-binding protein 1 (CD2BP1) gene and the Majeed syndrome, characterized by chronic recurrent multifocal osteomyelitis, congenital dyserythropoietic anemia, and neutrophilic dermatosis caused by mutations of the LPIN2 gene. Finally, a recently identified autosomal recessive autoinflammatory syndrome, due to the Deficiency of the interleukin-1–receptor antagonist (DIRA), is characterized by a neonatal onset multifocal osteomyelitis, periostitis, and skin pustulosis.

 Table I

Diseases

Gene
Chromosome

Protein

Transmission

Clinical features

 Periodic/recurrent  Fevers

Familial Mediterranean fever

 MEVF
16p13.3

Pyrin

AR

Short duration of fever episodes: 24-48 hours.
Abdominal and chest pain. Erysipelas-like erythema.
High incidence of renal amyloidosis in untreated patients.
Good response to Colchicine.
Possible response to IL-1 blockade

Mevalonate kinase deficency

 MVK
12q24

Mevalonate kinase

AR

Early onset (usually < 12 months).
Mean duration of fever episodes: 4-5 days
Poor conditions during fever episodes. Abdominal pain, vomiting and diarrhoea. Splenomegaly.
Good response to steroids. High rate of self-resolution during adulthood. Amyloidosis is rare.

TNF receptor associated periodic syndrome

TNFRSF1A
12p13

p55 TNF receptor

AD

Prolonged fever episodes: 1-3 weeks  
Periorbital edema, monocytic fasciitis.
Incidence of renal amyloidosis: 15-25%.
Response to TNF- and IL-1 blockade

NLRPs-related diseases

FCAS, MWS, CINCA

CIAS1/NALP3/NLRP3
1q44

Cryopyrin

AD

FCAS: rash, fever and arthralgia after cold exposure.
MWS: recurrent or sub-chronic urticaria-like lesions,  sensorineural hearing loss, amyloidosis
CINCA: as above + mental retardation, chronic aseptic meningitis and bone deformities
Good response to IL-1 blockade

NLRP12-associated Periodic Fever

NALP12/NLRP12
19p13

NLRP12

AD

Periodic fever after cold exposure, hearing loss

Granulomatous disorders

Blau’s syndrome

CARD15/NOD2 16q12

CARD15

AD

Early onset (< 5 years)
Polyarticular granulomatous arthritis, uveitis, skin rash
Good response to anti-TNF monoclonal antibodies

Pyogenic disorders

PAPA syndrome

PSTPIP1
15q24-q25.1

PSTPIP1

AD

Pyogenic sterile arthritis, pyogenic gangrenosum, Cystic acne. Good response to IL-1 blockade.

Majeed’s syndrome

 LPIN2
18p

LPIN2

AR

Multifocal osteomyelitis, congenital dyserythropoietic anemia, inflammatory dermatosis

DIRA

IL1RN
2q

IL1 receptor antagonist

AR

Neonatal-onset multifocal osteomyelitis, periostitis, and pustulosis. Dramatic response to Anakinra.

FCAS: Familiar Cold Autoinflammatory Syndrome; MWS: Muckle-Wells Syndrome; CINCA: Chronic Infantile Neurological Cutaneous and Articular Syndrome; PAPA:  Pyogenic Sterile Arthritis, Pyoderma Gangrenosum and Acne (PAPA) syndrome;  CRMO: chronic recurrent multifocal osteomyelitis; DIRA (deficiency of the interleukin-1–receptor antagonist); AR: autosomal recessive; AD: autosomal dominant.