Autoinflammatory Syndromes Flashcards
Which syndrome is associated with erysipeloid erythema (an erythematous rash around the foot/ankle during flares)?
Familial Mediterannean Fever
What are key characteristics and treatment for Familial Mediterranean Fever?
- 1-3 days of fever with serositis, arthritis, or rash (erysipeloid erythema).
- peritonitis, amyloidosis
- Jewish, Armenian, Arab, Turkish, Italian are high risk
- recessive mutations in MEFV (encodes pyrin)
- Tx: colchicine, IL-1 inhibitors
What are key characteristics and treatment for TNF Receptor-Associated Periodic Syndrome (TRAPS)?
-fever for up to weeks (longest fever episodes of autoinflammatory syndromes), serositis, rash
-migratory rash and periorbital edema are characteristic
-DOMINANT mutations in TNFRSF1A
-renal amyloidosis
Tx: Colichicine usu NOT EFFECTIVE however corticosteroids, etanercept, and IL-1 blockade (anakinra, canakinumab) are effective in various settings
*adalimumab, infliximab cause FLARE of disease (monoclonal antibodies against TNF)
What are key characteristics and treatment for Hyper-IgD with periodic fever syndrome (HIDS)?
-always onset childhood w/ vaccinations; onset 1st year of life. Stress can trigger flares too.
-recessive mutations in MVK gene (mevalonate kinase), which is involved in cholesterol and steroid synthesis
-thought that a decrease in isoprenoids, such as geranyl pyrophosphate, leads to overproduction of IL-1beta
-painful cervical adenopathy, aphthous ulcers, abdominal pain, arthritis, rash
-amyloidosis is RARE
-Dutch, northern europeans
-Can have normal IgD. Serum IgD does not correlate with flares
Tx: IL-1 blockade (anakinra, canakinumab)
What are the 3 different CAPS diseases that are caused by mutations in CIAS1? (CIAS1 Associated Periodic Fever Syndromes).
FCAS - Familial Cold Autoinflammatory Syndrome
Muckle-Wells
NOMID/CINCA (neonatal onset multisystem inflammatory disease/chronic infantile neurological cutaneous and articular)
All 3 have fever + urticarial rash, mutations in NLRP3 aka CIAS1 (cryopyrin) –> excessive IL-1beta
What are key characteristics and treatment for FCAS - Familial Cold Autoinflammatory Syndrome?
-Dominant mutations in CIAS1 aka NLRP3 (cryopyrin)
-fever, urticarial rash: Flare with generalized exposure to cold–negative ice cube test but positive evaporative cooling test
-Rash 2hrs after exposure, last 12 hrs
-Not true urticaria: neutrophils, not mast cells
-Onset usu in first 6 mo of life, can be right after delivery (cold room)
-Amyloidosis is rare
Tx: IL-1 inhibition (Anakinra)
What are key characteristics and treatment for Muckle-Wells Syndrome?
-Dominant mutations in CIAS1 aka NLRP3 (cryopyrin)
-fever, urticarial rash
-arthritis
-sensorineural deafness
-amyloidosis
Tx: IL-1 inhibition
What are key characteristics and treatment for NOMID/CINCA (Neonatal Onset Multisystem Inflammatory Disease)
-Dominant mutations in CIAS1 aka NLRP3 (cryopyrin)
-fever, urticarial rash
-bony overgrowth
-CNS disease (papilledema, chronic meningitis, hearing loss)
Tx: IL-1 inhibition
What are key characteristics and treatment for DIRA (deficiency of IL-1 receptor antagonist)?
- neonatal onset
- systemic inflammation (elevation ESR, CRP, cytokine)
- multifocal osteomyelitis
- periosteitis
- skin pustulosis (discrete lesions to confluent lesions)
- RESPONSE TO ANAKINRA HUGE
What are key characteristics and treatment for PAPA syndrome?
- Pyogenic Arthritis
- Pyoderma gangrenosum
- Acne - cystic and scarring
- Dominant mutation in PSTPIP1 (interacts with pyrin to cause increased IL-1beta activation)
- Tx: steroids, TNF blockade, IL-1 blockade
What are key characteristics and treatment for DADA2 syndrome?
- AR mutation in CECR1 -> deficiency in ADA2
- intermittent fevers
- early onset lacunar strokes (recurrent) and other neurologic issues
- livedoid rash
- systemic vasculopathy (lots of TNF deposition in blood vessels), polyarteritis nodosa
- mild immunodeficiency (esp IgM)
- hematologic abnormalities
- TNF blockade may help prevent strokes
- anticoag and anti-platelet therapies should be AVOIDED
- BMT may be helpful in some
What are key characteristics and treatment for CANDLE (Chronic Atypical Neutrophilic Dermatosis with Lipodystrophy and Elevated temperatures) syndrome?
-excessive type 1 interferon production from mutation in proteasome subunit beta type 8
-nodular erythema
-panniculitis
-lipoatrophy, intra-abdominal fat deposition
-myositis
-Basal ganglion and soft tissue calcifications
Tx: JAK kinase inhibitors
What are key characteristics of SAVI (STING associated vasculopathy in infancy)?
- vasculitis
- gangrene
- lung fibrosis
What are key characteristics and treatment for PFAPA (Periodic Fevers with aphthous stomatitis, pharyngitis, and adenitis)?
- most common periodic fever syndrome in children
- no gene identified yet
- duration 3-6 days, every 3-8 weeks often with strict “clockwork” periodicity
- dramatic response to steroids, can give as a “test”
- tonsillectomy can cause temporary cessation
- cimetidine helpful in 30% of pts
- intermittent anakinra helpful in aborting episodes
- children tend to outgrow this
What are key characteristics and treatment for Behcet’s Disease?
-oral ulcerations, eye lesions, skin lesions, genital ulcerations
-Dx criteria: recurrent oral ulcers at least 3x/year, plus two of the following
-recurrent genital ulcers
-eye lesions (uveitis or retinal vasculitis)
-skin lesions (e. nodosum, papulopustular lesions or acneiform nodules)
-pathergy (exaggerated skin injury)
-Assoc with: GI disease (diarrhea, abd pain, ulcerations), neurologic disease, vascular disease, HLA-B51 prevalence, haploinsufficiency of A20 (HA20)
Tx: colchicine, prednisone, targeted organ manifestations
Blau syndrome presents as uveitis, synovitis, skin rash, cranial neuropathies, and association with Crohn’s disease.
What causes Blau syndrome?
mutations in NOD2 gene that may interfere with the binding of NOD2 protein, a member of the NLRC family, to bacterial cell-wall components and subsequent signaling through NF-kB.
What are key characteristics and treatment of PLAID - phospholipase-C-γ-2-associated antibody deficiency and immune dysregulation?
-autosomal dominant mutation in PLCγ2: diminished signaling at physiologic temps (antibody deficiency) but enhanced signaling at cold temps (cold urticaria).
-negative ice cube test, positive evaporative cooling test
-75% of pts with recurrent sinopulm infections
-50% show autoimmunity and allergic disease
Tx: high-dose antihistamines for urticaria; Ig replacement therapy
Amyloidosis occurs with chronic inflammatory conditions, and is caused by deposits of Ig light chains in primary amyloidosis (AL), or deposits of acute-phase reactants and serum amyloid A (AA) protein in tissues with secondary amyloidosis.
How is amyloidosis identified in tissue biopsy?
Congo-red-positive deposits in abdominal fat pad/tissue biopsy, seen as apple green birefringence under polarized light.
