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1. Rheum RC > Autoinflamm / AOSD > Flashcards

Autoinflamm / AOSD Flashcards

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1
Q

** AOSD manifestations **

A

(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

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2
Q

Double quotidian fever ddx

A

-AOSD
-Kawasaki
-Kala-azar
-Mixed Malaria
-TB (miliary)
-Gonococcal endocarditis

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3
Q

AOSD Rash description

A

Evanescent (elicited w/ heat eg fever, shower)
-Salmon colored,
-Macular/maculopapular,
-Nonpruritic
-Koebner phenomenon

-Can be atypical w/ urticaria

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4
Q

AOSD rash biopsy

A

Dermal edema
-Perivascular mononuclear cell infiltrate

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5
Q

AOSD lab features

A

-Ferritin>1000ng/mL
-Soluble IL-2 R
-Increased liver enzymes
-Hypoalbuminemia, Anemia
-Increased ESR/CRP, WBC (neut), Plt

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6
Q

High ferritin DDX

A

-AOSD, MAS
-SLE, CAPS
-Infection (HIV, TB, CMV), Septic shock
-Cancer (Breast, lung, liver, colon, prostate, melanoma, lymphoma, liver mets)

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7
Q

Pathophys high ferritin in AOSD

A

IL6, IL18, TNF induce heme degrading enzyme (heme oxygenase) on macrophages and endothelial cells →
- Iron release from heme →
- Ferritin synthesis

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8
Q

AOSD pathophys

A

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

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9
Q

** Yamaguchi criteria including exclusions**

A

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

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10
Q

Unusual AOSD Derm manifestations

A

Alopecia
-Mucosal ulcers
-Subcut nodules

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11
Q

AOSD Unusual Cardiac Manifestations

A

Myopericarditis
Tamponade
Heart block

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12
Q

AOSD Unusual Pulm Manifestations

A

Pharyngitis
-ILD
-pHTN

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13
Q

AOSD Unusual GI Manifestations

A

Necrotizing lymphadenitis (Kikuchi) – >A abdo pain
-Acute liver failure

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14
Q

AOSD Unusual Heme Manifestations

A

-Hemolytic anemia
-TTP
-MAS, DIC

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15
Q

AOSD Unusual Neuro Manifestations

A

Aseptic meningitis
-Sensorineural hearing loss
-Periph neuropathy
-Amyotrophy

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16
Q

AOSD Unusual Ocular Manifestations

A

Orbital pseudotumor
-Uveitis

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17
Q

AOSD Unusual Renal Manifestations

A

Interstitial nephritis
-Amyloidosis

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18
Q

AOSD Tx

A

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

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19
Q

AOSD biologic options

A

AntiTNF (better for chronic articular w/ few systemic)

-IL1i (anakinra, canakinumab, rilonacept)
-IL6i (toci) better for systemic

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20
Q

Other options in AOSD if resistant to 1st line biologics

A

RItux,
-Abatacept,
-IVIG,
-Stem cell transplant

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21
Q

Poor prognostic signs for chronic AOSD

A

Polyarthritis
-Large joint involvement (shoulder/hip)
-Elevated ferritin at onset

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22
Q

Cause of death Stills

A

-Infxn
-Heme: DIC, TTP, MAS
-Status epilepticus
-ARDS
-Liver/heart failure
-Amyloid

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23
Q

** Diff between MAS and AOSD **

A

-Fever nonremitting
-Rapid cytopenias due to phagocytosis of hematopoeitc cells by macrophages in BM and reticulendothelial system
-Hemorrhagic manifestations: DIC, GIB,
-HyperTG

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24
Q

** MAS lab abnormalities **

A

Cytopenias
-High ferritin, TG, soluble IL2R (CD25)levels
-High liver enzymes,
-Consumptive coagulopathy (DIC w/ high PT),
-Low fibrinogen → LOW ESR,

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25
MAS pathology
BM aspirate and biopsies of LN, liver, spleen show hemophagocytosis by macrophages
26
MAS Tx
High dose GC -Cyclosporine -Etoposide -Biologics (IL1i, TNFi) -DMARD (MTX, AZA, MMF) -IVIG
27
MAS IX
PCR for active EBV or other viral (CMV, Parvo)
28
Characteristics of AutoInflamm
INNATE immune system (no autoantibodies) -Antigen INDEPENDENT (no infxn or autoimmunity) -Periodic fever
29
** Autoinflamm or periodic fever pathogenesis **
Genetic defect causes inappropriate activation of **INNATE** immune system → - -- **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
30
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
31
** 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
32
** 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
33
** 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)
34
** Autoinflamm syndromes by genes **
FMF = MEFV (pyrin) -TRAPs = TNFR1 -HIDS - MVK -CAPS - NLRP3 (cryopyrin)
35
Sx of Schnitzler
**-IgM gammopathy** **-Urticarial rash** - Dermatographism -Bone pain -Fever -HSM, LN -Heme malignancy
36
** 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)
37
Tx of ESRD 2/2 AA
Renal transplant -Continuation of colchicine
38
** 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
39
** FMF complication **
Amyloid
40
** FMF Tx**
Colchicine 1.8mg/d (PREVENTS flares, reduces amyloid risk and progression of nephrotic syndrome & proteinuria) -IL1Bi - anakinra and canakinumab
41
**Colchicine side effects**
GI intolerance (N/V/D) -Renal insuff -Cytopenias -Neuromyopathy -Toxicity → BM failure, rhabdo, circ collapse, AKI, resp failure
42
**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%
43
**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**)
44
TRAPS Tx
NSAIDs if mild -Prednisone during flares -**Etanercept, Infliximab** -Anakinra, Canakinumab -**COLCHICINE NOT EFFECTIVE**
45
** 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
46
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
47
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
48
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
49
HIDS Tx
NSAIDs Colchicine Steroids IVIG -Cyclosporine -Etanercept IL1 blocker: Anakinra, Canakinumab -Simvastatin
50
Cryopyrin assoc’d periodic syndromes examples
NOMID -FCAS -MWS
51
CAPS autoinflammatory pathophysiology
NLRP3 Cryopyrin gain of fcn mutation → persistent activation of inflammasome and increase in proinflamm cytokines eg IL1B
52
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 -
53
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
54
FCAS mimicker and how to differentiate
Acquired cold urticaria -Ice cube test negative (immed skin change after contact)
55
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
56
MWF Clinical features
-Fever, Headache -Urticarial rash -Arthralgia > arthritis -Conjunctivitis/episcleritis, -Sensorineural hearing loss -Limb pain -Renal AA
57
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
58
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
59
CAPS autoinflamm Tx
**IL1B: anakinra, canakinumab, rilonacept** -Short term: NSAID, antihistamine, prednisone -NO BENEFIT FROM COLCHICINE
60
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
61
PAPA clinical features
Pyogenic sterile arthritis, -Pyoderma gangrenosum, -Cystic acne (at puberty) -No amyloid risk -Fever NOT prominent
62
PAPA Tx
GC -IL1 ANT: anakindra
63
** 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
64
** Blau clinical features **
-Fever -Cranial neuropathies -**Anterior/panUVEITIS** -Tenosynivits/Polyarthritis (multiple interphalangeal contractures) -Granulomatous dermatitis -LVV
65
** Blau Tx**
NSAIDs -Low dose GC -Infliximab -Anakinra
66
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
67
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
68
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
69
CANDLE Clinical features
Fever, Cardiomyopathy, Conjunctivitis/episcleritis Arthropathy, ANNULAR rash, Aseptic meningitis, Nothing Distrophy (lipo), Delay (growth, Diarrhea) Lip swelling, Hepatomegaly,
70
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
71
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
72
How to dx autoinflamm
Pattern recognition -Fever diary -Exclude other causes -Empiric medication trial -Genetic testing
73
**MC autoinflamm syndrome vs MC monogenic autoinflamm syndrome **
PFAPA -Vs -FMF
74
**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
75
**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
76
**PFAPA Tx and PPX**
NSAIDs -Prednisone 1-2mg/kg x1 dose at fever onset (repeated once after 24h if still febrile) -Tonsillectomy -Cimetidine -Colchicine
77
Chronic recurrent multifocal OM disease association
Seronegative: IBD, ank spond, psoriasis Palmoplantar pustulosis (SAPHO) -Pustular acne -Pyoderma gangrenosum
78
CRMO sx and pattern
Focal bone pain (worse at night) - long bone metaphyses, vertebrae, clavicle, pelvis -+/- Fever -Unifocal, multifocal -Monophasic, recurrent, or unrelenting
79
CRMO onset and when it resolves
Onset 7-12 (can be adult onset); resolve by adolescence
80
** 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
81
** 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)
82
** 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).

1. Rheum RC (23 decks)

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