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1. Rheum RC > Autoinflamm / AOSD > Flashcards

Autoinflamm / AOSD Flashcards

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
Q

MAS pathology

A

BM aspirate and biopsies of LN, liver, spleen show hemophagocytosis by macrophages

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26
Q

MAS Tx

A

High dose GC
-Cyclosporine
-Etoposide
-Biologics (IL1i, TNFi)
-DMARD (MTX, AZA, MMF)
-IVIG

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27
Q

MAS IX

A

PCR for active EBV or other viral (CMV, Parvo)

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28
Q

Characteristics of AutoInflamm

A

INNATE immune system (no autoantibodies)
-Antigen INDEPENDENT (no infxn or autoimmunity)
-Periodic fever

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29
Q

** Autoinflamm or periodic fever pathogenesis **

A

– 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

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30
Q

Autoinflamm manifestations

A

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

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31
Q

** Recurrent fever DDX**

A

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

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32
Q

** 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?**

A

FMF
-TRAPS
-CHILDHOOD HIDS
-CAPS (FCAS, MWS, NOMID)
-PFAPA
-PAPA
-Blaiu
-DIRA

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33
Q

** Autoinflamm by fever duration **

A

<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
Q

** Autoinflamm syndromes by genes **

A

FMF = MEFV (pyrin)
-TRAPs = TNFR1
-HIDS - MVK
-CAPS - NLRP3 (cryopyrin)

35
Q

Sx of Schnitzler

A

-IgM gammopathy
-Urticarial rash - Dermatographism
-Bone pain

-Fever
-HSM, LN
-Heme malignancy

36
Q

** FMF**
– Inheritance (gene, protein)
– High risk ethnic popln & age
– Duration of attack in days and freq of attacks
– Amyloid risk
-

A

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
Q

Tx of ESRD 2/2 AA

A

Renal transplant
-Continuation of colchicine

38
Q

** FMF clinical features **

A

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
Q

** FMF complication **

A

Amyloid

40
Q

** FMF Tx**

A

Colchicine 1.8mg/d (PREVENTS flares, reduces amyloid risk and progression of nephrotic syndrome & proteinuria)
-IL1Bi - anakinra and canakinumab

41
Q

Colchicine side effects

A

GI intolerance (N/V/D)
-Renal insuff
-Cytopenias
-Neuromyopathy
-Toxicity → BM failure, rhabdo, circ collapse, AKI, resp failure

42
Q

TRAPS (TNF R assocd periodic syndrome)
– Inheritance (gene, protein)
– High risk ethnic popln & age
– Duration of attack in days
– Amyloid risk
-

A

Dominant or de novo (TNFRSF1A - TNF R type 1)
-ANY group <20yo
-**1-3weeks q4-6wks
-Amyloid in 10%

43
Q

**TRAPS clinical features **

A

~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
Q

TRAPS Tx

A

NSAIDs if mild
-Prednisone during flares
-Etanercept, Infliximab
-Anakinra, Canakinumab

-COLCHICINE NOT EFFECTIVE

45
Q

** Similarities and differences between FMF and TRAPS **

A

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
Q

HIDS (hyperimmunoglobulin D syndrome)
– Inheritance (gene, protein)
– High risk ethnic popln & age
– Duration and freq of attacks
– Amyloid risk
-

A

Recessive (MVK, mevalonate kinase → increased IL1B from mononuclear cells)
-Age <1 in dutch/french/european
-3-7days every 4-6-wks
-Amyloid RARE

47
Q

HIDS clinical features

A

-Fevers, cervical adenopathy
-Aphthous ulcers (oral, genital)
-Headache
-Rash (Maculopapular, papular, morbilliform, palpable purpura, erythema elevatum diutinum)
-Arthritis
-Splenomegaly, Abdo pain, N/V

48
Q

HIDS lab features

A

High inflamm markers
-Urinary mevalonic acid increased during flares
-High IgD levels (not necessary for dx) can stay high between flares
-IgA elevated

49
Q

HIDS Tx

A

NSAIDs
Colchicine
Steroids
IVIG

-Cyclosporine
-Etanercept
IL1 blocker: Anakinra, Canakinumab

-Simvastatin

50
Q

Cryopyrin assoc’d periodic syndromes examples

A

NOMID
-FCAS
-MWS

51
Q

CAPS autoinflammatory pathophysiology

A

NLRP3 Cryopyrin gain of fcn mutation → persistent activation of inflammasome and increase in proinflamm cytokines eg IL1B

52
Q

FCAS (familial cold autoinflamm syndrome)
– Inheritance (gene, protein)
– High risk ethnic popln & age
– Duration of attack in days
– Amyloid risk
-

A

Dominant
-Age <1 yo in Europeans
-Lasts hours to 2-3d (MC <24h) (mildest form of CAPS)
-Renal AA RARE
-

53
Q

FCAS clinical features

A

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
Q

FCAS mimicker and how to differentiate

A

Acquired cold urticaria
-Ice cube test negative (immed skin change after contact)

55
Q

MWF (muckle wells syndrome)
– Inheritance (gene, protein)
– High risk ethnic popln & age
– Duration of attack in days
– Amyloid risk
-

A

Dominant
-Childhood-Adolescent (Northern Europeans)
-Variable duration/freq: avg = 2-3d (Intermed severity in CAPS presentation)
-++ amyloid risk

56
Q

MWF Clinical features

A

-Fever, Headache
-Urticarial rash
-Arthralgia > arthritis
-Conjunctivitis/episcleritis,

-Sensorineural hearing loss
-Limb pain

-Renal AA

57
Q

NOMID (neonatal onset multisystem inflamm dz)
– Inheritance (gene, protein)
– High risk ethnic popln & age
– Duration of attack in days
– Amyloid risk

A

Dominant or de novo
-At BIRTH or early infancy
-Symptoms CONTINUOUS (MOST severe CAPS)
-+ amyloid risk

58
Q

NOMID Symptoms

A

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
Q

CAPS autoinflamm Tx

A

IL1B: anakinra, canakinumab, rilonacept

-Short term: NSAID, antihistamine, prednisone

-NO BENEFIT FROM COLCHICINE

60
Q

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
-

A

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
Q

PAPA clinical features

A

Pyogenic sterile arthritis,
-Pyoderma gangrenosum,
-Cystic acne (at puberty)
-No amyloid risk

-Fever NOT prominent

62
Q

PAPA Tx

A

GC
-IL1 ANT: anakindra

63
Q

** Blau aka early onset sarcoid **
– Inheritance (gene, protein)
– High risk ethnic popln & age
– Duration of attack in days
– Amyloid risk

A

Dominant (NOD2 gene, NOD 2prot)

-<3-5 yo in ANY ethnic group

-Variable duration of attacks

-Rare amyloid

64
Q

** Blau clinical features **

A

-Fever
-Cranial neuropathies
-Anterior/panUVEITIS

-Tenosynivits/Polyarthritis (multiple interphalangeal contractures)

-Granulomatous dermatitis
-LVV

65
Q

** Blau Tx**

A

NSAIDs
-Low dose GC
-Infliximab
-Anakinra

66
Q

DIRA (Def IL1 R ANT)
– Inheritance (gene, protein)
– High risk ethnic popln & age
– Duration of attack in days
– Clinical features
– Amyloid risk
-

A

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
Q

DITRA (def IL36R ANT)
– Inheritance (gene, protein)
– High risk ethnic popln & age
– Duration of attack in days
– Clinical features
– Amyloid risk
-

A

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
Q

CANDLE (chronic atypical neutrophilic dermatosis w/ lipodystrophy & elevated temp)
– Inheritance (gene, protein)
– High risk ethnic popln & age
– Duration of attack in days
– Amyloid risk

A

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
Q

CANDLE Clinical features

A

Fever,

Cardiomyopathy, Conjunctivitis/episcleritis
Arthropathy, ANNULAR rash, Aseptic meningitis,
Nothing
Distrophy (lipo), Delay (growth, Diarrhea)
Lip swelling,

Hepatomegaly,

70
Q

DADA2 (def of adenosine deaminase)
– Inheritance (gene, protein)
– High risk ethnic popln & age
– Duration of attack in days
– Clinical features
– Amyloid risk
-

A

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
Q

Explain how NLRP3 inflammasome is relevant in autoinflamm syndromes

A

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
Q

How to dx autoinflamm

A

Pattern recognition
-Fever diary
-Exclude other causes
-Empiric medication trial
-Genetic testing

73
Q

**MC autoinflamm syndrome vs MC monogenic autoinflamm syndrome **

A

PFAPA
-Vs
-FMF

74
Q

**PFAPA **
– Inheritance (gene, protein)
– High risk ethnic popln & age
– Duration of attack in days / freq
– Clinical features
– Amyloid risk
-

A

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
Q

How to dx PFAPA

A

Dx of Exclusion
-Sent when well and during episode: CBC, ESR, CRP, strep culture, ferritin, liver enzymes, albumin, LDH, IGs, UA

76
Q

PFAPA Tx and PPX

A

NSAIDs
-Prednisone 1-2mg/kg x1 dose at fever onset (repeated once after 24h if still febrile)
-Tonsillectomy

-Cimetidine
-Colchicine

77
Q

Chronic recurrent multifocal OM disease association

A

Seronegative: IBD, ank spond, psoriasis
Palmoplantar pustulosis (SAPHO)
-Pustular acne
-Pyoderma gangrenosum

78
Q

CRMO sx and pattern

A

Focal bone pain (worse at night) - long bone metaphyses, vertebrae, clavicle, pelvis
-+/- Fever

-Unifocal, multifocal
-Monophasic, recurrent, or unrelenting

79
Q

CRMO onset and when it resolves

A

Onset 7-12 (can be adult onset); resolve by adolescence

80
Q

** CRMO Dx and findings**

A

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
Q

** CRMO Tx (1st line and refractory) **

A

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
Q

** Explain the meaning of the following acronyms, and give a brief description of the conditions.
-a. FMF
-b. RS3PE
-c. PMR
-d. MRH **

A

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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