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AA-Amyloidosis
D N b t Bl kDr. Norbert Blank
Division of RheumatologyChair: Prof. H.-M. Lorenz
Internal Medical Clinic 5Chair and Director: Prof. A. D. Ho
University of HeidelbergUniversity of Heidelberg
AA-Amyloid in deep rectal biopsy
(Prof. Röcken, Charite, Berlin)
secondary AA-Amyloidosiscan be associated with any chronic-inflammatory disease
rheumatoid diseases:rheumatoid arthritisjuvenile idiopathic arthritisankylosing spondylitis (Bechterew)psoriatic arthritispconnective tissue diseases, vasculitis
RA SpA
PsoA
bronchiectasiapulmonary fibrosis
pulmonary cavernaeWegener‘s granulomatosis
pulmonary fibrosissystemic sclerosis
pyoderma gangraenosumpyoderma gangraenosum
secondary AA-Amyloidosiscan be associated with any chronic-inflammatory disease
rheumatoid diseases:rheumatoid arthritisjuvenile idiopathic arthritisankylosing spondylitis (Bechterew)psoriatic arthritispconnective tissue diseases, vasculitis
periodic fever syndromesperiodic fever syndromes
gastrointestinal diseases: Crohn‘s disease, Colitis ulcerosa, Whipple‘s disease
chronic pulmonary diseases:COPD, mucoviszidosis, bronchiektasia
chronic infections:infected ulcers, decubiti, osteomyelitis, skin abscesses, tuberculosis
periodic fever syndromes
FMFfamilial
HIDSHyper-IgD-Syndromemediteranean
fever
Hyper-IgD-Syndrome„dutch fever“
TRAPSTNFReceptor associated periodic syndrome„hibernian fever“ MWS„hibernian fever MWS
Muckle-Wells-Syndrome
CINCANOMID
FCASfamilial cold
autoinflammatoryBlau-Syndromeearly onset sarcoidosis NOMID autoinflammatory
syndromey
CAPS : Cryopyrin-associated periodic syndrome :
FCAS : familial cold autoinflammatory syndrome = FCU
MWS : Muckle-Wells-Syndrome
CINCA: chronic inflammatory neuro-cutaneous arthritis syndrome
1st episode < 1. year
NOMID: newborn onset multisystemic inflammatory disease
variable fever episodes, arthralgia, arthritis
Urticaria ca 2-3h after cold exposition
p y
Urticaria ca. 2 3h after cold exposition
CNS involvement: sterile meningtitis, cephalgia, nausea and vomitingtransient-permanent hearing loss
AA amyloidosis
p g
clinical spectrum of CIAS1 = NLRP3 mutations
CINCA=
NOMID Muckleon tom
s
NOMID MuckleWells
Syndromefamilialfla
mm
atio
ns s
ympt
familialcold urticaria
sity
of i
nfin
ical
sig
Inte
nsC
RP,
cli
CAPS
CAPS
Kötter I, Schedel J, Kümmerle-Deschner JB.Periodic fever syndrome/autoinflammatory syndrome. Z Rheumatol 2009
CAPS : FCAS / MWS / CINCA-NOMID:
ASC=apoptosis-associated speck like protein containing a CARDBBCC=B box and a coiled coilSPRY=B30.2 domainNACHT=NAIP, CIITA, HETE and TP-1 : NOD1,2, IPAF, NALPsPAMP=pathogen associated molecular patternPAMP=pathogen-associated molecular pattern
Yu et al, Cell Death Differ, 2006
Patient with CINCAAzathioprine 50-100mg/die + prednisone MMF200
IL1RA IL1RAIL1RA
AdaIL1RA
EtanerceptEtanercept
150150
[mg/
l]
100
CR
P [
50
0
2 3 3 3 3 04 04 04 4 05 05 05 5 06 06
01.1
1.02
01.0
2.0
01.0
5.0
01.0
8.0
01.1
1.0
01.0
2.0
01.0
5.0
01.0
8.0
01.1
1.0
01.0
2.0
01.0
5.0
01.0
8.0
01.1
1.0
01.0
2.0
01.0
5.0
local reactions to anakinra (Kineret®)
MWS-CINCA overlap syndrome treated with Canakinumab (anti-IL1)
200
250
(mg/
l)
CRPSAA
80
100
(mg/
l)
100
150SAA
(
40
60 CR
P
50
100SAA = 2.5x CRP
20
40
0
d+1
d+2
d+3
d+8
d+38
d+68
+82,
d+1
d+2
d+8
d+38
d+68
+73,
d+1
d+2
d+8
d+38
+68,
d+1
d+2
d+8
+68,
W0 XT W4
W8
W16
07 07 07 07 07 07 07 07 08 08 08 08 08 08 08 08 08 08 08 08 08 08
0
d+ d+ d+ d+
24.1
0.0
26.1
0.0
29.1
0.0
06.1
1.0
07.1
1.0
08.1
1.0
13.1
1.0
18.1
2.0
17.0
1.0
31.0
1.
01.0
2.0
07.0
2.0
12.0
3.0
17.0
4.0
22.0
4.
23.0
4.0
29.0
4.0
27.0
5.0
24.0
6.
25.0
6.0
01.0
7.0
19.0
8.
28.0
8.0
16.0
9.0
14.1
0.0
10.1
2.0
Period-1 Period-2 Period-3 Period-4Anakinrawash outwash-out
ACZ885-A2102ACZ885-D2306
Therapeutic targets in chronic inflammatory diseases
the cytokine network
TNF- IL-1++
IL-2
- -
IL-6
+ + +
- -
IL-4IL-13 IL-10
the role of IL-6 in the cytokine network Th1-cytokines induce IL-6, Th2-cytokines inhibit IL-6.Adapted from Tackey et al., Lupus 2004.
Target Type of drug
Etanercept TNF-α TNF-Receptor-IgG-constructInfliximab TNF-α chimeric monoclonal antibodyAdalimumab TNF-α human monoclonal antibodyGolimumab TNF-α human monoclonal antibodyCertolizumab TNF α pegylated Fab2 antibody fragmentCertolizumab TNF-α pegylated Fab2- antibody fragment
Anakinra IL-1 recombinant human IL-1-ReceptorantagonistRil t IL 1 IL 1 R t I G t t IL 1 tRilonacept IL-1 IL-1-Receptor-IgG-construct, IL-1-trapCanakinumab IL-1 human monoclonal antibody
Tocilizumab IL-6R humanized monoclonal antibodyRituximab CD20 chimeric monoclonal antibody, B cell depletionAb t t B7 CTLA4 I G t t bl k ti l tiAbatacept B7 CTLA4-IgG-construct, blocks costimulation
Summary / Conclusion:
AA amyloidosis (AAA) is a rare long term complication of chronic inflammatory diseasesof chronic inflammatory diseases
screening procedures reveal a higher incidence of AAAscreening procedures reveal a higher incidence of AAA
ftreatment with biologics probably reduce the risk for AAA and inhibit progression of manifest AAA