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