Auto Inflammatory Diseases Flashcards
Autoimmune diseases have what?
Do what?
What immunity?
Classic examples?
High-titer autoantibodies and/or auto reactive antigen-specific T cells
Destructive immune response to self antigens
Adaptive immunity
Lupus, Grave’s disease
Autoinflammatory diseases do not have what?
have episodes of what?
what immunity?
prototype diease?
NO high titer autoantibodies or auto reactive, antigen specific T cells
Have episodes of seemingly unprovoked inflammation that sometimes results in tissue destruction
innate immunity!!
FMF (familial mediterranean fever)
PAMPS?
DAMPS?
PRR?
pathogen associated molecular patterns (LPS/viral RNA)
danger associated molecular patterns (can be produced by our own cells when stressed)
Pattern Recognition Receptors - recognize both PAMPs and DAMPs
- cell surface (TLRs)
- intracellular (NALPs)
Autoinflammatory disease have a spontaneous activation of the innate pathway that leads to NFkB stimulation, leading to translation of many pro-inflammatory cytokines!
…
What is the pathway for innate immunity reactions?
Infection
Recognition of PAMPs
Inflamm, recruitment, and activation of effector cells,
removal of infectious agent
What is the pathway for autoinflamm disorders?
inborn error of the innate immune system
too sensitive to minor stimuli and/or turned off too late
inflamm, recruitment, and activation of effector cells
dysregulation of inflamm cytokines IL-1B, TNF-alpha, IL-6
AUTOINFLAMMATORY DISORDER
What is the definition of auto inflammatory disorders?
important slide!!
memorize!!!
recurrent episodes of inflammation not associated with infection or malignancy…
It has these symptoms:
FEVER is prominent
Multisystem involvement (joints, skin, GI tract, eyes)
Sometimes nontraditional triggers (temperature, stress, exercise, menstruation)
LACK OF high-titer auto-antibodies or antigen specific T cells (lack of T and B lymphocytes)
Predominance of MONOCYTES AND NEUTROPHILS rather than lymphocytes as effector cells
Examples of hereditary periodic fever syndromes?
Familial mediterranan fever (FMF)
TRAPs
HIDs
See slide for more
Examples of idiopathic febrile syndromes?
PFAPA
Granulomatous diseases?
crohn’s
blau syndrome
early onset sarcoidosis
see slide for complement, etc disorders!
..
Familial Mediterranean Fever
Genetics? Episodes of fever with...? Duration? Interval between episodes? Variable risk for what?
Inherited, autosomal recessive
Episodes of fever associated with localized inflammation
- skin
- serosal membranes
- joints
- biopsies from affected tissues show infiltration with mainly neutrophils
Duration: from days to weeks
Variable intervals between episodes
- residual inflammatory activity in some patients
Variable risk for amyloidosis
Inflammation of FMF almost looks like infectious cellulitis but not - only has neutrophils and lacks lymphocytes
Inflammation is STERILE!
…
There is increased risk for amyloidosis in FMF when there is subclinical inflammation that does that fully resolve in-between episodes
…
What is the gene responsible for FMF?
What does it encode?
What are the domains of its protein?
MEFV
Encodes the pyrin protein
Four domains of pyrin:
- PYRIN domain
- zinc finger domain
- coil-coiled domain
- c-term domain
What is the function of the pyrin domain?
what is it a member of?
pyrin domain is shared by a number of proteins involved in apoptosis and inflammation
member of a large family of intracellular PRPs that link sensing of intracellular microbial products to the proteolytic processing of pro-ILB to its active form….. (NALP3)
NALP3 also has a pyrin domain
…
Pyrion protein – HAS ABILITY TO REGULATE THE FORMATION OF THE NALP3 INFLAMMASOME! – FMF PATIENTS HAVE A GAIN OF FUNCTION MUTATION IN THE PYRION PROTEIN THAT CAUSES INCREASES FORMATION OF THE NALP3 INFLAMMASOME! – SPONTANEOUS ACTIVATION OF IL-1B
….
NALP3 Associated Autoinflammatory syndromes have what mutations?
How many syndromes?
What is the genetics?
Mechanism?
Mutations in the NACHT domain of the NALP3
Leads to at least 3 auto inflammatory syndromes
autosomal dominant pattern of inheritance
spontaneous assembly of NALP3 inflammasome
NALP3 inflammasome leads to activation of caspase which leads to pro-IL1B to IL1B
…
What are the three NALP3 (CIAS1)-Associated Autoinflammatory disorders?
NACHT domain mutations
Muckle-Wells Syndrome (MWS)
Familial Cold Autoinflammatory Syndrome (FCAS)
Neonatal Onset Multisystem inflammatory disease or NOMID
FCAS is a what phenotype?
mild!
cold-induced urticaria, fever, athralgia
MWS is a what phenotype?
intermediate
urticaria
amyloidosis
deafness
NOMID is a what phenotype?
severe!
neonatal onset urticaria
CNS disease
arthropathy
Familial Cold (Urticaria) Autoinflammatory Syndrome (FCAS)
urticaria presentation?
duration?
symptoms?
Urticaria >30 min after general cold exposure
- Generalized (i.e. not limited to cold-exposed areas)
- Local cold exposure is not a trigger (distinguishes from acquired urticaria)
Duration 12-72 hours
Fever, chills, malaise, arthralgias
Joint stiffness
Profuse sweating
Extreme thirst
What is the urticaria like in FCAS?
relatively flat - not as elevated like in allergy and do NOT have flare
not pruitic (tender, NOT itchy)
very painful
Muckle-Wells Syndrome
age of onset? episode length? what is a trigger? symptoms? uriticaria? big risk?(2)
Variable age at onset
Relatively short episodes (12-72 hours) - more frequent than FCAS
Temperature changes as a trigger
Chills, fever, malaise
Urticaria-like rash
“aching”, not pruritic
Progressive sensori-neural hearing loss (1/3 of pts)
Amyloidosis in up to 25% (why want to tx aggressively)
Neonatal Onset Multisystem Inflammatory Disease (NOMID)
First symptoms when? What is the rash like? CNS disease? Sensory anomalies? Anthropathy?
memorize slide!!
First symptoms – early in infancy
Rash
- often present at birth
- non pruritic urticaria
- perivascular neutrophilic infiltrate in skin biopsy (true in last two syndromes)
CNS disease
- chronic non-infectious meningitis (mainly neutrophils in SF)
- Increased intracranial pressure
- Low IQ
Sensory anomalies:
- Perceptive deafness!!
- optic nerve atrophy !!
Arthropathy:
- Arthritis during flares
- Overgrowth of the epiphysieal plate resulting in bone enlargement!!
- Progressive contractures due to deformity
NALP3 - associated periodic fever syndromes:
what are they responsive to for tx?
IL-1 inhibition!
What are the three IL-1 blocking agents?
Anakinra - recombinant IL-1Ra
Canakinumab - fully human monoclonal antibody with IL-1B specificity
Rilonacept - IL-1 Trap: dimeric fusion protein composed of extracelllular domains of human IL-1R1 and IL-1RAcP linked to Fc portion of IgG1
What does Anakinra do?
Recombinant IL-1Ra
Binds to IL-1R1, blocks IL-1beta and IL-1alpha activity
What does canakinumab do?
Fully human monoclonal antibody with IL-1β specificity
Neutralizes IL-1β
What does Rilonacept do?
IL-1 Trap: dimeric fusion protein composed of extracellular domains of human IL-1R1 and IL-1RAcP linked to Fc portion of IgG1
Neutralizes IL-1β and IL-1α
How common are MWS, FCUS, and NOMID?
Rare!
The pathophysiology underling these diseases is relevant to several more common conditions though
Gout is recurrent attacks of what?
Caused by what?
Where does it occur?
Recurrent attacks of acute inflammatory arthritis
Caused be elevated levels of uric acid which may crystallize
Crystals are deposited in joints, tendons and surrounding tissues (crystals function as DAMP! - IL-1beta created!)
IL-1 inhibition has been proven to help in gout!
….
Chronic Recurrent Multifocal Osteomyelitis (CRMO)
recurrent what?
associated with what?
bone biopsy shows what?
memorize slide!!!
Recurrent multifocal lytic bone lesions with swelling and pains: Distal tibia Pelvis Proximal tibia Metatarsals Vertebral bodies Clavicle
The inflammation may extend to surrounding soft tissues
Often associated with fevers
Various number of lesions at each flare (1-7) – why called “multi focal” – looks like they have osteomyelitis!
Bone biopsy shows non-specific chronic inflammation – “sterile” – have neutrophils! – similar to other auto-inflammatory diseases!
CRMO looks like white spots on bones of MRI
…
CRMO…
periodic exacerbations and remissions
variable durations and intervals of episodes
long term outcome?
overlap with what?
long term outcome is unclear… but a sizable proportion of pts continue to have episodes for many years
overlap with IBD
once they hit puberty, usually fine
CRMO - spectrum to monogenic to likely polygenic conditions
…
What is the tx for CRMO?
NSAIDs
Steroids, MTX
TNF-inhibiting agents
IL-1 inhibiting may be better? (no clinical trails)
TRAPS… what does it stand for?
genetics?
mechanism?
TNF receptor associated periodic syndrome
autosomal dominant
associated with not turning off pathway when infection cleared
TRAPS
duration? intervals? trigger? onset? rash type? what is commonly involved? what is rare? myalgias? what is characteristic???
memorize slide!!
Relatively long duration of the episodes (1-4 weeks)
Variable intervals between attacks
Physical trauma is a common trigger
Early onset (3-5 years of age)
Migratory erythematous rash
Serosal involvement common:
- Peritoneal adhesions
Arthritis rare
Myalgias
- Panniculitis, fasciitis, occasionally myositis
Conjunctivitis, periorbital swelling (inflamm regions in eyelids)
TRAPS rash looks relatively benign but what is actually going on?
inflammation extends deeper into the soft tissues (go to fat and to muscle - see MRI) - very painful!!
Pt won’t be able to move - “TRAPed and cannot move”
May also have fevers
What is the mechanism of auto inflammation in TRAPS?
Impaired Receptor Shedding in TRAPS!
Normally there is a protease that cleaves the TNF receptor… The soluble part that is in the ECM can capture left over TNF to prevent it from binding….
How it stops signaling once infection has been cleared
In TRAPS, there is a problem with the protease OR an intracellular portion that spontaneous activates without receptor
What is the tx for intracellular TRAPS mechanism?
IL-1beta inhibitors
What is the tx for TRAPS shedding mechanism?
Enbrel (etanercept) - creates soluble TNF receptors that bind TNF before it reaches receptor
doesn’t work for spontaneous intracellular mechanism
TRAPS tx overall?
Etanercept (enbrel)
Some pts respond better to IL-1 inhibiting agents
What is the most common auto inflammatory syndrome in children?
Syndrome of periodic fever with apthous stomatitis, pharyngitis, and cervical adenopathy (PFAPA)
NOT FAMILIAL!
PFAP Diagnostic Criteria (memorize) - RELATIVELY BENIGN CONDITION! - outgrow it usually by puberty
Regularly recurring what?/onset?/duration?
constitutional symptoms in the absence of what?
At least one of the following symptoms..?
Asymptomatic intervals between episodes!!
Normal growth and development!!
Exclusion of what?
Regularly recurring fevers (>38.3oC) usually with early age of onset (<5 y/o)
- Duration 3-5 days
Constitutional symptoms in the absence of URI
With at least one of the following symptoms:
Aphthous stomatitis
Lymphadenitis (typically cervical)
Pharyngitis
Asymptomatic intervals between episodes
Normal growth and development
Exclusion of cyclic neutropenia or other intermittent fever syndromes
What do you have to be worried about when a child presents with PFAPA symptoms?
That it might not be PFAPA!
Could be cyclic neutropenia, etc! (more severe - so be worried)
Cyclic Neutropenia….
Inherited how?
Typical cycle?
During attacks have what?
What are pts susceptible to?
Inherited form caused by mutations in the ELA2 gene (neutrophil elastase-2)
Typical cycle 21 days
During attacks ANC <200
-Low normal between the episodes
While neutropenic, pts are susceptible to infections
- Mucosal ulcerations, gingivitis, LAD, fever
What are additional features of PFAPA that are not included in the PFAPA criteria?
What do these features overlap with?
Abdominal pain Diarrhea Joint and muscular pains Rash Genital ulcers
These features overlap with FMF, TRAPS, HIDS and Behcet’s syndrome
while it might look like PFABA, need to monitor because it might turn out to be something more sever like FMF or Behcet’s
…
If it is classic PFAPA, what tx will it respond to?
IL-1B agents! (anakinra)
What is the general approach with patients with periodic fevers?
important!
Periodicity (truly cyclic?)
Duration
Associated symptoms
Any reasons to suspect one of the inherited syndromes?
CBC on several occasions (r/o cyclic neutropenia)
Degree of inflammatory activity
- during episodes
- returns to normal between episodes? – if not, more likely to develop amyloidosis
Overall growth and development
Resolve by the time of the beginning of puberty?
**Abdominal pain/diahhrea — take these pts more seriously if they have PFABA bc these are the ones that develop into things much worse
