Autoinflammatory diseases
The concept of autoinflammation was introduced in 1999 to describe a category of systemic
inflammation, exemplified by the monogenic periodic fever syndromes, that was distinct
from autoimmunity - first mentioned at the paper describing TRAPS, although pyrin was
identified in 1997.
Autoinflammatory diseases arise through inappropriate activation of antigen-
independent inflammatory mechanisms. Thus, they may broadly be considered to represent
primary diseases of innate immunity, although cells associated with adaptive immunity (ex.
lymphocytes) may also contribute to autoinflammation. These diseases typically lack
autoantibodies or MHC associations and occur as commonly in males as in females.
1. Disorders of inflammasomes and related IL-1 family cytokine
2. Diseases of interferon production and signalling. Autoantibodies as in SLE
and ANCA vasculitides may be encountered.
3. Diseases of NF-kB activation and/or TNF activity: represents a final common
pathway for many cell-activating stimuli. The proteins that make up the NF-kB complex
reside in inactive form in the cytoplasm. When released from inhibition, this complex
migrates to the nucleus to induce transcription of a network of proinflammatory genes.
4. Via other mechanisms (DADA2, COPA, APLAID).
Manifestations may include fever, rash, serositis (pleuritis or peritonitis), arthritis, meningitis
and uveitis. Lymphadenopathy and splenomegaly may also occur and secondary amyloidosis
(SAA) can complicate longstanding disease, also enterocolitis, vasculitic rash, basal ganglia
calcifications, stroke including cerebrovascular hemorrhage and ILD. Most patients develop
earliest disease manifestations in childhood, although milder or atypical forms can present
de novo in adults.
Autoinflammatory syndromes associated Autoinflammatory disorders that do not
with fever include: have fever as a major manifestation:
-FMF
-TRAPS -DIRA: osteomyelitis, periostitis, pustulosis
-HIDS -PAPA syndrome
-CAPS -Blau syndrome (juvenile systemic
granulomatosis)
-DADA2: that can present with stroke
-DITRA: that causes generalized pustular
psoriasis
Intrinsic inflammasomopathies represent molecular lesions in the constituent proteins of the
complex, while extrinsic inflammasomopathies denote disorders of various upstream or
downstream regulatory elements.
Ex. of intrinsic inflammasomopathies: CAPS
Ex. of extrinsic inflammasomopathies: FMF
While FMF is the prototypic autoinflammatory disease, the effect of the underlying disease-
causing mutations on IL-1β production may be primarily extrinsic to the inflammasome.
Pyroptosis is an inflammatory programmed cell death, where gasdermin-D (cleaved by
caspase-1) pokes holes in the cell membrane, rupture and release of IL-1 and IL-18. It is
effective against intracellular pathogens and is the opposite of apoptosis or autophagy
which is a cytoprotective process by which the cell sequesters damaged proteins, organelles
,or pathogens in a double membrane compartment, the autophagosome, targets this cellular
material for degradation in the lysosome and recycles the constituent molecules.
*Of periodic fever syndromes, only FMF and PFAPA have true periodicity.
Death domains: signal transduction and protein oligomerization in inflammation and
apoptosis are often mediated by a group of protein-protein interaction domains, the so-
called ‘death domain’ superfamily. This family currently comprises four members, the death
domain, the death effector domain, the caspase-recruitment domain (CARD) and the PYRIN
domain. Both pyrin and cryopyrin share an N-terminal motif, the PYRIN domain, that
facilitates protein-protein interactions. Another member of this superfamily, the death
domain, is found at the N-terminus of the protein mutated in TRAPS, the p55 TNF receptor
(TNFRSF1A). As discussed here, through their respective PYRIN and death domains,
cryopyrin, pyrin and the p55 TNF-R play an important role in regulating cytokine secretion,
NF-kB activation and apoptosis and thereby the innate immune system.
Systemic amyloidosis is one of the most serious manifestations of these diseases and is the
result of the tissue deposition of misfolded fragments of serum amyloid A. Most frequently,
deposition occurs in the kidneys, gastrointestinal tract, adrenals, spleen, testes and lung and
sometimes in the liver, heart and thyroid. In the pre-colchicine era, amyloidosis was a
frequent cause of death in patients with FMF.
Mosaicism arises through the development of disease-causing mutations after the single-cell
stage of embryogenesis. The proportion and distribution of cells bearing the mutation vary
depending upon when the mutation occurs. If the mutation arises at an early stage, the
resulting cells can be widely distributed, potentially even encompassing the germ cells and
thus transmissible to future offspring (so-called gonosomal mosaicism). Genetic divergence
arising later is usually restricted to non-gonadal cells (somatic mosaicism) and even to
specific cell populations. In such cases, the mutation can be missed if screening is restricted
to a cell population different from the ones affected or if the mutated cell population is only
a small fraction of the cells tested, such that the "signal" from cells bearing the mutation is
swamped by a larger fraction of non-mutant cells. Detection of such cases may require
specialized techniques, including next-generation DNA sequencing (deep sequencing) of
multiple tissues and generation of clones from different tissues from the same patient.
Fever of unknown origin
Definition (Petersdorf and Beeson, 1961)
-Fever >38.3°C
-Duration of fever >3 weeks
-Uncertain diagnosis after 1 week of hospital investigation
Patterns
-Tertian or quartan fever: prolonged malaria
-Undulant fever (evening, resolving by morning): brucellosis
-Week-long fevers with week-long remissions: borreliosis (Lyme and other)
-Periodic fevers: cyclic neutropenia, autoinflammatory
-Double quotidian fever (2 spikes/day): Still, malaria and typhoid
, Still
75% of patients are 16-35yrs, prevalence 0.1-0.4/100.000, although there’s no consensus for
incidence or prevalence. Male=female, slightly more female. Incidence vary from 1.6-4/106.
AOSD may be a reactive syndrome in which various infectious agents may act as disease
triggers in a genetically predisposed host. sJIA and AOSD belong to the same spectrum and
now the common name is Still’s disease. IL-18 is also elevated in AOSD and the elevation
appears to be more specific for AOSD than for other systemic rheumatic diseases. These
patients exhibit a specific, mild NLRP3 inflammasome dysregulation.
Etiology: multigenic autoinflammatory, but also monogenic LACC mutation.
i) genetics: HLA, mutations in the LACC gene have been associated with a familial pattern of
inheritance of a disease resembling Still's. LACC1 is crucial for autophagy in macrophages.
ii) infectious: EBV, CMV, parvovirus B19, rubella, mumps, echovirus 7, HHV 6, parainfluenza
virus, Coxsackie, adenovirus, Yersinia enterocolitica, Chlamydia pneumonia, Borrelia,
Mycoplasma.
Clinical: triad of high spiking fevers (>39°C) + evanescent rash + arthritis/arthralgia;
however there’s pleiotropic manifestation.
patterns: i) monocyclic (40%): lasts <1yr, with complete resolution of symptoms,
ii) polycyclic (10%): ≥2 flares with complete remission between episodes. Subsequent flares
tend to be less severe and of shorter duration than the initial episode, iii) chronic (50%):
persistently active disease associated with destructive arthritis.
Fever: the classic fever pattern is 1-2 daily spikes ≥39°C, most often
occurring late during the day (afternoon or evening) and receding spontaneously within
hours. However, continuous fever or early morning spikes are seen in up to 20%. Symptoms
The concept of autoinflammation was introduced in 1999 to describe a category of systemic
inflammation, exemplified by the monogenic periodic fever syndromes, that was distinct
from autoimmunity - first mentioned at the paper describing TRAPS, although pyrin was
identified in 1997.
Autoinflammatory diseases arise through inappropriate activation of antigen-
independent inflammatory mechanisms. Thus, they may broadly be considered to represent
primary diseases of innate immunity, although cells associated with adaptive immunity (ex.
lymphocytes) may also contribute to autoinflammation. These diseases typically lack
autoantibodies or MHC associations and occur as commonly in males as in females.
1. Disorders of inflammasomes and related IL-1 family cytokine
2. Diseases of interferon production and signalling. Autoantibodies as in SLE
and ANCA vasculitides may be encountered.
3. Diseases of NF-kB activation and/or TNF activity: represents a final common
pathway for many cell-activating stimuli. The proteins that make up the NF-kB complex
reside in inactive form in the cytoplasm. When released from inhibition, this complex
migrates to the nucleus to induce transcription of a network of proinflammatory genes.
4. Via other mechanisms (DADA2, COPA, APLAID).
Manifestations may include fever, rash, serositis (pleuritis or peritonitis), arthritis, meningitis
and uveitis. Lymphadenopathy and splenomegaly may also occur and secondary amyloidosis
(SAA) can complicate longstanding disease, also enterocolitis, vasculitic rash, basal ganglia
calcifications, stroke including cerebrovascular hemorrhage and ILD. Most patients develop
earliest disease manifestations in childhood, although milder or atypical forms can present
de novo in adults.
Autoinflammatory syndromes associated Autoinflammatory disorders that do not
with fever include: have fever as a major manifestation:
-FMF
-TRAPS -DIRA: osteomyelitis, periostitis, pustulosis
-HIDS -PAPA syndrome
-CAPS -Blau syndrome (juvenile systemic
granulomatosis)
-DADA2: that can present with stroke
-DITRA: that causes generalized pustular
psoriasis
Intrinsic inflammasomopathies represent molecular lesions in the constituent proteins of the
complex, while extrinsic inflammasomopathies denote disorders of various upstream or
downstream regulatory elements.
Ex. of intrinsic inflammasomopathies: CAPS
Ex. of extrinsic inflammasomopathies: FMF
While FMF is the prototypic autoinflammatory disease, the effect of the underlying disease-
causing mutations on IL-1β production may be primarily extrinsic to the inflammasome.
Pyroptosis is an inflammatory programmed cell death, where gasdermin-D (cleaved by
caspase-1) pokes holes in the cell membrane, rupture and release of IL-1 and IL-18. It is
effective against intracellular pathogens and is the opposite of apoptosis or autophagy
which is a cytoprotective process by which the cell sequesters damaged proteins, organelles
,or pathogens in a double membrane compartment, the autophagosome, targets this cellular
material for degradation in the lysosome and recycles the constituent molecules.
*Of periodic fever syndromes, only FMF and PFAPA have true periodicity.
Death domains: signal transduction and protein oligomerization in inflammation and
apoptosis are often mediated by a group of protein-protein interaction domains, the so-
called ‘death domain’ superfamily. This family currently comprises four members, the death
domain, the death effector domain, the caspase-recruitment domain (CARD) and the PYRIN
domain. Both pyrin and cryopyrin share an N-terminal motif, the PYRIN domain, that
facilitates protein-protein interactions. Another member of this superfamily, the death
domain, is found at the N-terminus of the protein mutated in TRAPS, the p55 TNF receptor
(TNFRSF1A). As discussed here, through their respective PYRIN and death domains,
cryopyrin, pyrin and the p55 TNF-R play an important role in regulating cytokine secretion,
NF-kB activation and apoptosis and thereby the innate immune system.
Systemic amyloidosis is one of the most serious manifestations of these diseases and is the
result of the tissue deposition of misfolded fragments of serum amyloid A. Most frequently,
deposition occurs in the kidneys, gastrointestinal tract, adrenals, spleen, testes and lung and
sometimes in the liver, heart and thyroid. In the pre-colchicine era, amyloidosis was a
frequent cause of death in patients with FMF.
Mosaicism arises through the development of disease-causing mutations after the single-cell
stage of embryogenesis. The proportion and distribution of cells bearing the mutation vary
depending upon when the mutation occurs. If the mutation arises at an early stage, the
resulting cells can be widely distributed, potentially even encompassing the germ cells and
thus transmissible to future offspring (so-called gonosomal mosaicism). Genetic divergence
arising later is usually restricted to non-gonadal cells (somatic mosaicism) and even to
specific cell populations. In such cases, the mutation can be missed if screening is restricted
to a cell population different from the ones affected or if the mutated cell population is only
a small fraction of the cells tested, such that the "signal" from cells bearing the mutation is
swamped by a larger fraction of non-mutant cells. Detection of such cases may require
specialized techniques, including next-generation DNA sequencing (deep sequencing) of
multiple tissues and generation of clones from different tissues from the same patient.
Fever of unknown origin
Definition (Petersdorf and Beeson, 1961)
-Fever >38.3°C
-Duration of fever >3 weeks
-Uncertain diagnosis after 1 week of hospital investigation
Patterns
-Tertian or quartan fever: prolonged malaria
-Undulant fever (evening, resolving by morning): brucellosis
-Week-long fevers with week-long remissions: borreliosis (Lyme and other)
-Periodic fevers: cyclic neutropenia, autoinflammatory
-Double quotidian fever (2 spikes/day): Still, malaria and typhoid
, Still
75% of patients are 16-35yrs, prevalence 0.1-0.4/100.000, although there’s no consensus for
incidence or prevalence. Male=female, slightly more female. Incidence vary from 1.6-4/106.
AOSD may be a reactive syndrome in which various infectious agents may act as disease
triggers in a genetically predisposed host. sJIA and AOSD belong to the same spectrum and
now the common name is Still’s disease. IL-18 is also elevated in AOSD and the elevation
appears to be more specific for AOSD than for other systemic rheumatic diseases. These
patients exhibit a specific, mild NLRP3 inflammasome dysregulation.
Etiology: multigenic autoinflammatory, but also monogenic LACC mutation.
i) genetics: HLA, mutations in the LACC gene have been associated with a familial pattern of
inheritance of a disease resembling Still's. LACC1 is crucial for autophagy in macrophages.
ii) infectious: EBV, CMV, parvovirus B19, rubella, mumps, echovirus 7, HHV 6, parainfluenza
virus, Coxsackie, adenovirus, Yersinia enterocolitica, Chlamydia pneumonia, Borrelia,
Mycoplasma.
Clinical: triad of high spiking fevers (>39°C) + evanescent rash + arthritis/arthralgia;
however there’s pleiotropic manifestation.
patterns: i) monocyclic (40%): lasts <1yr, with complete resolution of symptoms,
ii) polycyclic (10%): ≥2 flares with complete remission between episodes. Subsequent flares
tend to be less severe and of shorter duration than the initial episode, iii) chronic (50%):
persistently active disease associated with destructive arthritis.
Fever: the classic fever pattern is 1-2 daily spikes ≥39°C, most often
occurring late during the day (afternoon or evening) and receding spontaneously within
hours. However, continuous fever or early morning spikes are seen in up to 20%. Symptoms
