Autoinflammatory diseases and fever syndromes - Twitter summary from #CSACI 2013 meeting

This is the last summary from the series covering the 2013 #CSACI meeting.

Dr. Ron Laxer discussed autoinflammatory diseases and fever syndromes.

“Too much” adaptive immune activity leads to autoimmunity. “Too much” innate immune activity leads to autoinflammation. Autoimmune diseases are abnormalities of the adaptive immune system, autoinflammatory diseases are abnormalities of innate immunity.

Auto inflammation is defined by relapsing and remitting bouts of inflammation, often without specific triggers.


Autoinflammatory diseases involve the "inflammasomes" which activate spontaneously to produce damage. This tendency is genetic.

NLRP3 Inflammasome is the best studied of all the 'inflammasomes" - NOD-like receptor, caspase and IL-1B are important.

Intracellular NOD-like receptor (NLR) activation by DAMPs may lead to activation of "inflammasomes".

IL-1B activation disorders are type 1 autoinflammatory diseases. NF-KB activation disorders are type 2 autoinflammation.

Mutations in NLRP3 result in "inflammasomopathies" and excess secretion of IL-1Beta.

IL-1 signaling is naturally kept in balance by IL-1 receptor antagonist. When this system is overwhelmed, the disturbance leads to inflammation. When homeostasis between IL-1 and IL-1RA is be upset, it leads to inflammation and autoinflammatory diseases.

IL-1B antagonists

IL-1B antagonists are being used to treat these autoinflammatory diseases. There are currently 3 different IL-1B antagonists on the market.

Medications targeting IL-1B are used in treatment of autoinflammatory diseases and include anakinra, rilonacept and canakinumab.

Anakinra is a receptor antagonist, Rilonacept is a soluble IL-1 trap, Canakinumab is a humanized monoclonal anti-IL-1B.

Anakinra is synthetic IL-1R antagonist, administered as daily SQ injection, and apparently the injections are painful.

Canakinumab is a humanized monoclonal antibody that prevents binding of IL-1b to its receptor, the half life is 3-4wks, and SC injections are q 8 wks.

Periodic Fever Syndromes

There are 3 are cryopyrin associated periodic syndromes "CAPS". One example is Muckle Wells Syndrome (MWS).

NLRP3 mutation in the inflammasome is the cause of these autoinflammatory conditions.

Familial Mediterranean Fever (FMF)

Periodic fever syndromes present with recurrent fevers of 3 weeks duration, separated by 1 week of good health. FMF is the prototype disorder. Familial Mediterranean Fever is the prototypical autoinflammatory disease. Flares usually only 3 to 4 days.

FMF is an autosomal recessive disorder, the mutation is in MEFV - pyrin is the abnormal protein in the inflammasome. The ethnic groups of Armenians, Turks, Sephardic Jews and Arabs are the main groups that develop FMF, hence the name.

FMF treatment is with colchicine and IL-1 blockade (e.g. anakinra).

IL-1 targeting therapies have been shown to be effective for different forms of CAPS (cryopyrin associated periodic syndromes).

CAPS include Familial Cold Autoinflammatory Syndrome (FCAS), Muckle Wells Syndrome and NOMID (neonatal onset multisystem inflammatory disease). These three exist on a spectrum, with FCAS being the mildest, and NOMID the most severe. There are several overlap syndromes along the spectrum.

Key features to assist in diagnosis of a periodic fever syndrome are:

- age of onset
- duration
- frequency
- triggers
- family history (FHx)
- ethnicity

Hyper- IgD syndrome

In mevalonate kinase deficiency (hyperImmunoglobulin D syndrome (HIDS) flares last 7-8 days, and vaccines can trigger symptoms.

Clinical presentation can include vasculitic rash, oral ulcers, joint and abdominal pain, and fevers. The rash of HIDS is usually erythematous macules, and occasionally painful urticaria.

There is no specific treatment currently for HIDS.

TNFR associated periodic syndrome (TRAPS)

TNFR associated periodic syndrome (TRAPS) is the only autoinflammatory disease that presents in adulthood. The flares always last more than 1 wk.

TRAPS symptoms include conjunctivitis, periorbital edema, migratory erythematous rash (occasionally urticarial) and fever.

Testing for auto inflammatory syndromes is typically done in Canada by sending specific inflammatory markers to US centres.

A common theme in all of these autoinflammatory syndromes is that in general they respond to IL-1 inhibition. Canakinumab (anti-IL-1 beta) can result in rapid improvement in such chronic autoinflammatory diseases.

There recommended review article on autoinflammatory diseases is in Allergy 2012; 67: 1465-74. Krause’s article in Allergy 2012 reviews the diagnosis of auto inflammatory disorders and how they can masquerade as urticaria.


PFAPA has no associated gene mutation, and it is the most common periodic fever syndrome. Most pediatric allergists see a few cases each year.

In PFAPA, there are no triggers. The patient (a child) presents with fever, aphthous stomatitis, pharyngitis, adenitis. They are well between episodes. PFAPA has a very predictable cycle.

PFAPA is the most common auto inflammatory syndrome with fever aphthous ulcers pharyngitis and adenitis. The prognosis is favorable, it gets better over time.

Corticosteroids work remarkably well for PFAPA, and this often helps to confirm the diagnosis.

PFAPA treatment consists of:

- oral steroids - very effective
- cimetidine
- colchicine
- anakinra
- tonsillectomy
- observation, it tends to improve over time

Twitter summary made possible by @IgECPD @allergydoc4kidz @DrAnneEllis

Three allergists did a great job posting updates from the 2013 meeting of the Canadian Society of Allergy and Clinical Immunology (#CSACI): @IgECPD @allergydoc4kidz @DrAnneEllis. Compared to year 2011, this represents 300% growth in Twitter use by the Canadian allergists (from one to three participants, stable since 2012.

For comparison, here are the tweets from the previous #CSACI meetings:

Sign up for 2014 #AAAAI Twitter list and meeting of tweeting allergists in real life (tweetup)

The AAAAI has the advantage of a larger membership base compared to #CSACI and not surprisingly ten times more allergists (30) posted Twitter updates from the 2012 #AAAAI meeting. The AAAAI is now on Twitter at @AAAAI_org

This is a list of the allergists who are planning to use Twitter to post updates from the 2014 #AAAAI meeting. The list is open for edit, please feel free to add your own info.

The list shows the availability of the allergists by date and if they are planning to attend a tweetup (meeting of people who use Twitter or are following the tweets). See you at 2014 #AAAAI meeting in sunny San Diego!

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