Autoinflamm / AOSD Flashcards
** AOSD manifestations **
(Double)/Quotidian fevers (>39 daily but returns to normal)
-Arthralgia/arthritis/myalgia
-Transient rash
-Prodromal sore throat (perichondritis of cricothyroid cartilage)
-LN, Weight loss, HSM
-Pleuritis/pericarditis
-Pneumonitis
-Abdo pain
Double quotidian fever ddx
-AOSD
-Kawasaki
-Kala-azar
-Mixed Malaria
-TB (miliary)
-Gonococcal endocarditis
AOSD Rash description
Evanescent (elicited w/ heat eg fever, shower)
-Salmon colored,
-Macular/maculopapular,
-Nonpruritic
-Koebner phenomenon
-Can be atypical w/ urticaria
AOSD rash biopsy
Dermal edema
-Perivascular mononuclear cell infiltrate
AOSD lab features
-Ferritin>1000ng/mL
-Soluble IL-2 R
-Increased liver enzymes
-Hypoalbuminemia, Anemia
-Increased ESR/CRP, WBC (neut), Plt
High ferritin DDX
-AOSD, MAS
-SLE, CAPS
-Infection (HIV, TB, CMV), Septic shock
-Cancer (Breast, lung, liver, colon, prostate, melanoma, lymphoma, liver mets)
Pathophys high ferritin in AOSD
IL6, IL18, TNF induce heme degrading enzyme (heme oxygenase) on macrophages and endothelial cells →
- Iron release from heme →
- Ferritin synthesis
AOSD pathophys
PAMP/DAMP binds TLR on macrophage/ neutrophil → inflammasome activation → caspase activation and overproduction of IL1B
-IL1B further activates macrophages/ neutrophils → more proinflamm cytokines (IL6,8,17,18, TNF)
-Regulatory antinflamm mech (reg T cells or IL10) may be defective
** Yamaguchi criteria including exclusions**
5+ (including at least 2 major):
-Major:
-Quotidian Fever 39 >1wk
-Arthralgia/arthritis >2 wks
-Salmon evanescent rash
-Leukocytosis >10k w/ >80% neuts
-Minor:
-Sore throat
-Lymphadenopathy
-Hepato or splenomegaly
-Abnormal liver enzymes
-NEGATIVE RF and ANA
-*Exclusion: SLE, infxn, Cancer, sweet’s, schnitzler, autoinflamm, D rxns
Unusual AOSD Derm manifestations
Alopecia
-Mucosal ulcers
-Subcut nodules
AOSD Unusual Cardiac Manifestations
Myopericarditis
Tamponade
Heart block
AOSD Unusual Pulm Manifestations
Pharyngitis
-ILD
-pHTN
AOSD Unusual GI Manifestations
Necrotizing lymphadenitis (Kikuchi) – >A abdo pain
-Acute liver failure
AOSD Unusual Heme Manifestations
-Hemolytic anemia
-TTP
-MAS, DIC
AOSD Unusual Neuro Manifestations
Aseptic meningitis
-Sensorineural hearing loss
-Periph neuropathy
-Amyotrophy
AOSD Unusual Ocular Manifestations
Orbital pseudotumor
-Uveitis
AOSD Unusual Renal Manifestations
Interstitial nephritis
-Amyloidosis
AOSD Tx
Mild (fever, arthralgia): Naproxen 500BID → pred 0.5/mg/kg/d if no fx s/p 2wks
-Mod (high fever, disabling arthritis, mild organ involvement): high dose pred 1mg/kg/d
– Add MTX if MSK and trouble tapering
-Severe (liver necrosis, tamponade, MAS, DIC): pulse steroids + early biologic
-Resistant (ongoing pred >20mg/d despite DMARD): Biologic
AOSD biologic options
AntiTNF (better for chronic articular w/ few systemic)
-IL1i (anakinra, canakinumab, rilonacept)
-IL6i (toci) better for systemic
Other options in AOSD if resistant to 1st line biologics
RItux,
-Abatacept,
-IVIG,
-Stem cell transplant
Poor prognostic signs for chronic AOSD
Polyarthritis
-Large joint involvement (shoulder/hip)
-Elevated ferritin at onset
Cause of death Stills
-Infxn
-Heme: DIC, TTP, MAS
-Status epilepticus
-ARDS
-Liver/heart failure
-Amyloid
** Diff between MAS and AOSD **
-Fever nonremitting
-Rapid cytopenias due to phagocytosis of hematopoeitc cells by macrophages in BM and reticulendothelial system
-Hemorrhagic manifestations: DIC, GIB,
-HyperTG
** MAS lab abnormalities **
Cytopenias
-High ferritin, TG, soluble IL2R (CD25)levels
-High liver enzymes,
-Consumptive coagulopathy (DIC w/ high PT),
-Low fibrinogen → LOW ESR,
MAS pathology
BM aspirate and biopsies of LN, liver, spleen show hemophagocytosis by macrophages
MAS Tx
High dose GC
-Cyclosporine
-Etoposide
-Biologics (IL1i, TNFi)
-DMARD (MTX, AZA, MMF)
-IVIG
MAS IX
PCR for active EBV or other viral (CMV, Parvo)
Characteristics of AutoInflamm
INNATE immune system (no autoantibodies)
-Antigen INDEPENDENT (no infxn or autoimmunity)
-Periodic fever
** Autoinflamm or periodic fever pathogenesis **
– Activates Inflamamsome and caspase 1 to cleave pro IL1b
– Excess IL1B production cause endothelial activation, hepatocyte and acute phase reactant production, and activation of NFkb activating IL1, 6, TNF
Autoinflamm manifestations
Continuous, irregular, or regular flares of fever, ESR/CRP/WBC, and sx involving joints, organs, skin, eyes
-Self resolving and asymptomatic w/ normal labs in btwn
** Recurrent fever DDX**
Cyclic neutropenia
-Hypothalamic dz
-Infection: hidden foci (eg aortoenteric), borrelia, malaria, whipple, recurrent reinfection (host defense defect, immunodeficiency)
-Noninfectious inflamm: behcet, sJIA/AOSD, sarcoid, IBD, Sweet, CRMO, Schnitzler
-Vascular - DVT/PE
-Ca: Leuk, lymphoma, solid tumor (pheo, neuroblastoma, colon, RCC), paraneoplastic
** Name five periodic fever syndromes. Name three presentations. Name two that present in childhood. Which part of the immune system is activated? What is the pathway?**
FMF
-TRAPS
-CHILDHOOD HIDS
-CAPS (FCAS, MWS, NOMID)
-PFAPA
-PAPA
-Blaiu
-DIRA
** Autoinflamm by fever duration **
<1d: FCAS
-1-3d: FMF or FCAS (<1y)/MWS (10-30yo)
-3-7d: HIDS or PFAPA
-7-21d: TRAPS
-Daily: sJIA (<16), AOSD or Schnitzler (16-35 yo)
** Autoinflamm syndromes by genes **
FMF = MEFV (pyrin)
-TRAPs = TNFR1
-HIDS - MVK
-CAPS - NLRP3 (cryopyrin)
Sx of Schnitzler
-IgM gammopathy
-Urticarial rash - Dermatographism
-Bone pain
-Fever
-HSM, LN
-Heme malignancy
** FMF**
– Inheritance (gene, protein)
– High risk ethnic popln & age
– Duration of attack in days and freq of attacks
– Amyloid risk
-
Recessive , MEFV gene, pyrin protein (increases IL1B activation and innate immune system activation)
-Jews, arabs, turks, armenian, italian <20yo
-1-3 days q2-4wk
-+++ risk of amyloid (2/2 chronic inflamm → renal failure and ESRD)
Tx of ESRD 2/2 AA
Renal transplant
-Continuation of colchicine
** FMF clinical features **
Fever
-Serositis: sterile peritonitis (abdo pain), pleuritis, pericarditis
-Rash: erysipelas like
-Arthritis: mono (hip, knee, ankle, wrist) > poly
-Amyloid
-Less common:
-Aseptic meningitis,
-Scrotal swelling, LN
** FMF complication **
Amyloid
** FMF Tx**
Colchicine 1.8mg/d (PREVENTS flares, reduces amyloid risk and progression of nephrotic syndrome & proteinuria)
-IL1Bi - anakinra and canakinumab
Colchicine side effects
GI intolerance (N/V/D)
-Renal insuff
-Cytopenias
-Neuromyopathy
-Toxicity → BM failure, rhabdo, circ collapse, AKI, resp failure
TRAPS (TNF R assocd periodic syndrome)
– Inheritance (gene, protein)
– High risk ethnic popln & age
– Duration of attack in days
– Amyloid risk
-
Dominant or de novo (TNFRSF1A - TNF R type 1)
-ANY group <20yo
-**1-3weeks q4-6wks
-Amyloid in 10%
**TRAPS clinical features **
~FMF
-Fever
-Rash: erysipelas (over trunk vs shins/feet in FMF)
-Serositis: peritonitis (~to FMF)
-Myalgia (MC thigh but can be other)
-Arthralgia > Arthritis (monoarthritis if present)
-Conjunctivitis (not in FMF)
-Periorbital edema (not in FMF)
TRAPS Tx
NSAIDs if mild
-Prednisone during flares
-Etanercept, Infliximab
-Anakinra, Canakinumab
-COLCHICINE NOT EFFECTIVE
** Similarities and differences between FMF and TRAPS **
Similarities:
-Fever, Erysipelas like rash, Serositis
-Elevated inflammatory markers
-Oral ulcers, Lymphadenopathy
Differences:
-Rash location: TRAPS - trunk → extremities, FMF = shins and feet
-MSK manifestations: Arthritis often present in FMF, often absent in TRAPs (arthralgias and myalgias) more common
-Conjunctivitis and periorbital swelling - present in TRAPS but not in FMF
-FMF: 1-3 days
-TRAPs: 1-3weeks
HIDS (hyperimmunoglobulin D syndrome)
– Inheritance (gene, protein)
– High risk ethnic popln & age
– Duration and freq of attacks
– Amyloid risk
-
Recessive (MVK, mevalonate kinase → increased IL1B from mononuclear cells)
-Age <1 in dutch/french/european
-3-7days every 4-6-wks
-Amyloid RARE
HIDS clinical features
-Fevers, cervical adenopathy
-Aphthous ulcers (oral, genital)
-Headache
-Rash (Maculopapular, papular, morbilliform, palpable purpura, erythema elevatum diutinum)
-Arthritis
-Splenomegaly, Abdo pain, N/V
HIDS lab features
High inflamm markers
-Urinary mevalonic acid increased during flares
-High IgD levels (not necessary for dx) can stay high between flares
-IgA elevated
HIDS Tx
NSAIDs
Colchicine
Steroids
IVIG
-Cyclosporine
-Etanercept
IL1 blocker: Anakinra, Canakinumab
-Simvastatin
Cryopyrin assoc’d periodic syndromes examples
NOMID
-FCAS
-MWS
CAPS autoinflammatory pathophysiology
NLRP3 Cryopyrin gain of fcn mutation → persistent activation of inflammasome and increase in proinflamm cytokines eg IL1B
FCAS (familial cold autoinflamm syndrome)
– Inheritance (gene, protein)
– High risk ethnic popln & age
– Duration of attack in days
– Amyloid risk
-
Dominant
-Age <1 yo in Europeans
-Lasts hours to 2-3d (MC <24h) (mildest form of CAPS)
-Renal AA RARE
-
FCAS clinical features
Cold induced urticaria (also erythematous macules/petechiae on extremities),
Arthralgia,
Conjunctivitis,
H/A,
Malaise,
Diaphoresis
-Renal AA RARE
-NO DEAFNESS, PERIORBITAL EDEMA, LN, SEROSITIS
FCAS mimicker and how to differentiate
Acquired cold urticaria
-Ice cube test negative (immed skin change after contact)
MWF (muckle wells syndrome)
– Inheritance (gene, protein)
– High risk ethnic popln & age
– Duration of attack in days
– Amyloid risk
-
Dominant
-Childhood-Adolescent (Northern Europeans)
-Variable duration/freq: avg = 2-3d (Intermed severity in CAPS presentation)
-++ amyloid risk
MWF Clinical features
-Fever, Headache
-Urticarial rash
-Arthralgia > arthritis
-Conjunctivitis/episcleritis,
-Sensorineural hearing loss
-Limb pain
-Renal AA
NOMID (neonatal onset multisystem inflamm dz)
– Inheritance (gene, protein)
– High risk ethnic popln & age
– Duration of attack in days
– Amyloid risk
Dominant or de novo
-At BIRTH or early infancy
-Symptoms CONTINUOUS (MOST severe CAPS)
-+ amyloid risk
NOMID Symptoms
Triad: urticarial rash, arthropathy, chronic aseptic meningitis
-Sensorineural hearing loss
-LN, HSM
-Growth restriction - saddle nose, protruding eyes, frontal bossing
-Focal epiphyseal overgrowth (can be confused w/ Ca)
-Renal AA can occur
CAPS autoinflamm Tx
IL1B: anakinra, canakinumab, rilonacept
-Short term: NSAID, antihistamine, prednisone
-NO BENEFIT FROM COLCHICINE
PAPA (pyogenic sterile arthritis, pyoderma gangrenosum, and acne syndrome)
– Inheritance (gene, protein, and mech)
– High risk ethnic popln & age
– Duration of attack in days
– Clinical features
– Amyloid risk
-
Dominant (CD2BP1, CD2 binding protein → hyperphosphorylation of PSTPIP1 → stronger interaction w/ pyrin –< more IL1B production)
-<10 yo in ANy ethnic group
-Variable duration of attacks
-No amyloid risk
PAPA clinical features
Pyogenic sterile arthritis,
-Pyoderma gangrenosum,
-Cystic acne (at puberty)
-No amyloid risk
-Fever NOT prominent
PAPA Tx
GC
-IL1 ANT: anakindra
** Blau aka early onset sarcoid **
– Inheritance (gene, protein)
– High risk ethnic popln & age
– Duration of attack in days
– Amyloid risk
Dominant (NOD2 gene, NOD 2prot)
-<3-5 yo in ANY ethnic group
-Variable duration of attacks
-Rare amyloid
** Blau clinical features **
-Fever
-Cranial neuropathies
-Anterior/panUVEITIS
-Tenosynivits/Polyarthritis (multiple interphalangeal contractures)
-Granulomatous dermatitis
-LVV
** Blau Tx**
NSAIDs
-Low dose GC
-Infliximab
-Anakinra
DIRA (Def IL1 R ANT)
– Inheritance (gene, protein)
– High risk ethnic popln & age
– Duration of attack in days
– Clinical features
– Amyloid risk
-
Recessive (IL-1RN, IL-1RA secretion lost → unchecked IL1 signalling )
-<4 weeks yo in Netherlands, Newfoundland, Lebanon, Puerto Rico
-Almost continuous attacks
-Pustulosis, pathergy, sterile OM, Periostitis at ends of ribs/long bones, respiratory distress. Fever typically absent
No amyloid
DITRA (def IL36R ANT)
– Inheritance (gene, protein)
– High risk ethnic popln & age
– Duration of attack in days
– Clinical features
– Amyloid risk
-
Recessive (IL36RN, IL36ra secretion lost → unchecked IL36 signaling )
-Variable age in any ethnic group
-Variable duration of attacks (days to weeks)
-Generalized pustular psoriasis (palms/soles) high fever, arthralgia, glossitis, nail dystrophy
CANDLE (chronic atypical neutrophilic dermatosis w/ lipodystrophy & elevated temp)
– Inheritance (gene, protein)
– High risk ethnic popln & age
– Duration of attack in days
– Amyloid risk
Recessive (PSMB8, protesome subunit B8 → abN interferonG response)
-At birth/infancy in various ethnicities
-Variable duration of attacks (Freq or continuous)
-No Amyloid risk
CANDLE Clinical features
Fever,
Cardiomyopathy, Conjunctivitis/episcleritis
Arthropathy, ANNULAR rash, Aseptic meningitis,
Nothing
Distrophy (lipo), Delay (growth, Diarrhea)
Lip swelling,
Hepatomegaly,
DADA2 (def of adenosine deaminase)
– Inheritance (gene, protein)
– High risk ethnic popln & age
– Duration of attack in days
– Clinical features
– Amyloid risk
-
Recessive (CECR1, ADA2 prot)
-Variable age of onset ( childhood) in unknown ethnic groups with variable duration of attacks
-Fever, livedo reticularis, early onset vasculopathy (stroke and/or polyarteritis nodosa (presentation), mild immunodeficiency
-No amyloid risk
Explain how NLRP3 inflammasome is relevant in autoinflamm syndromes
NLRP3 in neutrophils, monocytes and acts as intracellular sensor for PAMPs and DAMPs
– Forms NLRP3 inflammasome when stimulated with adaptor proteins ASC (pyrin and caspase activation domain) and Cardinal (interacts with NLRP3)
– This activates caspase from procaspase 1 to caspase 1 to activates proIL1B → IL1B
-
-Mutations at some of these prot → autoinflamm syndrome
How to dx autoinflamm
Pattern recognition
-Fever diary
-Exclude other causes
-Empiric medication trial
-Genetic testing
**MC autoinflamm syndrome vs MC monogenic autoinflamm syndrome **
PFAPA
-Vs
-FMF
**PFAPA **
– Inheritance (gene, protein)
– High risk ethnic popln & age
– Duration of attack in days / freq
– Clinical features
– Amyloid risk
-
NO GENETIC FACTORS
-Under 5yo (resolves by teens
-3-7d(~5), q28 days (2-8wks)
-Periodic Fever w/ Aphthous stomatitis, Pharyngitis, Adenitis
-NO AMYLOID risk
How to dx PFAPA
Dx of Exclusion
-Sent when well and during episode: CBC, ESR, CRP, strep culture, ferritin, liver enzymes, albumin, LDH, IGs, UA
PFAPA Tx and PPX
NSAIDs
-Prednisone 1-2mg/kg x1 dose at fever onset (repeated once after 24h if still febrile)
-Tonsillectomy
-Cimetidine
-Colchicine
Chronic recurrent multifocal OM disease association
Seronegative: IBD, ank spond, psoriasis
Palmoplantar pustulosis (SAPHO)
-Pustular acne
-Pyoderma gangrenosum
CRMO sx and pattern
Focal bone pain (worse at night) - long bone metaphyses, vertebrae, clavicle, pelvis
-+/- Fever
-Unifocal, multifocal
-Monophasic, recurrent, or unrelenting
CRMO onset and when it resolves
Onset 7-12 (can be adult onset); resolve by adolescence
** CRMO Dx and findings**
XR - mixed osteolytic sclerotic lesions, hyperostosis, vertebral body height loss, kyphosis
If XR negative, do MRI w/ STIR (> focal MRI or technetium bone scan) = increased STIR in BM and surrounding tissue w/ bony expansion
-Bone biopsy to confirm inflamm changes and to r/o infxn, malignancy
** CRMO Tx (1st line and refractory) **
No active spine lesions = NSAID
-Refractory to NSAID or spine lesion ⇒ DMARD (MTX or SFZ), OR
-TNFi (adalimumab, etanercept, infliximab) +/- MTX OR
-Bisphosphonates (pamidronate, ZA)
** Explain the meaning of the following acronyms, and give a brief description of the conditions.
-a. FMF
-b. RS3PE
-c. PMR
-d. MRH **
Familial Mediterranean Fever (FMF) is an inherited disease, characterized by recurrent attacks of fever, inflammation of the abdominal lining (peritonitis), inflammation of the lining surrounding the lungs , painful, swollen joints, and a characteristic ankle rash
-Remitting seronegative symmetrical synovitis with pitting edema (or sometimes RS3PE) is a rare syndrome identified by symmetric polyarthritis, synovitis, acute pitting edema (swelling) of the back of the hands and/or feet, and a negative serum rheumatoid factor.
-Polymyalgia rheumatica (PMR) is an inflammatory condition of the muscles and joints and is characterized by stiffness and pain in the neck, shoulders, hips, and buttocks. Morning stiffness that lasts several hours is common.
-Multicentric reticulohistiocytosis (MRH) is a rare disease in which papulonodular skin lesions containing a proliferation of true histiocytes (macrophages) are associated with arthritis that primarily affects the interphalangeal joints. MRH is not life threatening and, after an average course of 7-8 years, the disease often goes into remission. However, in 45% of cases, the associated arthritis may cause severe joint destruction known as arthritis mutilans. In addition to the joints, MRH can involve the bones, tendons, and muscles, as well as almost any organ (eg, the eyes, larynx, thyroid, salivary glands, bone marrow, heart, lungs, kidneys, liver, gastrointestinal tract).
