Kollagenosen Update 2017

Prof. Dr. Oliver Distler

Klinik für Rheumatologie

UniversitätsSpital Zürich

Wir decken die gesamte Rheumatologie ab

Alle rheumatologischen Tätigkeitsfelder

• Entzündliche Gelenkerkrankungen inkl. Ultraschall

• Degenerative Erkrankungen

• Lokale muskuloskelettale Erkrankungen

• Rückenerkrankungen

• Systemerkrankungen

• Biologika-Therapien

• Kapillarmikroskopie

• DEXA

• Wirbelsäuleninfiltrationen

• Stosswellen

Das neue Team in der Rheumatologie

Adrian CiureaArthritiden

Biologika

Britta MaurerKollagenosen und

Vaskulitiden

Lukas WildiArthrosen

Rückenerkrankungen

Sandra BlumhardtUltraschall

Wirbelsäuleninfiltrationen

Stosswellen

Diana FreyOsteoporose

Das neue Team in der Rheumatologie

Julio SanchezNotfallmedizin

Wirbelsäuleninfiltrationen

Stosswellen

Manuela di ChiaraLupus

UltraschallMike BeckerVaskulitiden

Kollagenosen

Andreas KrebsUltraschall

Multimodale Komplextherapie

15 Tage stationäre Intensivtherapie

Umfassendes muskuloskelettales Assessment

Analgetische Einstellung

Physiotherapie, Ergotherapie, Psychiatrie, Sozialdienst, ggf.

Neurochirurgie, Schmerzdienst

Aktive und passive Therapie, Haltungsschulung, Stabilisation

Patientenedukation

Universitäre Klinik für Rheumatologie

Abteilung für Physikalische

Medizin und Rheumatologie

Balgrist

Rheumaklinik

USZ

Forschung

Schlieren

Balgrist

EULAR Center of Excellence

KollagenosenChronisch-entzündliche Systemerkrankungen

• Systemische Sklerose

• Systemischer Lupus erythematodes (SLE)

• Polymyositis/Dermatomyositis

• Sjögren-Syndrom

• Mischkollagenose (U1-RNP-Antikörper)

• Undifferenzierte Kollagenose

• Overlap-Syndrome

Kollagenosen - Klassifikation

SLE Polymyositis SSc Sjögren MCTD

Raynaud-Phänomen

• Akut

• kurz (Minuten)

• bei Kälteexposition

• bicole oder tricolore (Diskussion: monocolore

Veränderungen)

Kein Raynaud-Phänomen

Allgemein kalte Hände

Bei Wärme werden meine Hände rot

Ich habe häufiger weissliche Verfärbungen

Meine Finger kribbeln, vor allem wenn ich mich aufrege

Im Zweifelsfall: Dokumentation (Smartphone)

Häufigkeit Raynaud bei

Kollagenosen

Mischkollagenose: Sehr, sehr häufig

Systemische Sklerose: Sehr, sehr häufig

Systemischer Lupus erythematodes: Seltener

Sjögren-Syndrom: Seltener

Polymyositis/Dermatomyositis: Seltener

Einfacher Ausschluss

Kollagenose bei Raynaud

1. Antinukleäre Antikörper, Spezifizierung

2. Kapillarmikroskopie

Beide negativ: < 1% Wahrscheinlichkeit

Eines positiv: 25% Wahrscheinlichkeit

Beide positiv: 75% Wahrscheinlichkeit

Kapillarmikroskopie zeigt

Mikroangiopathie

SSc

ANA: Immunfluoreszenz

Bestätigung: Spezifische ELISAs

A patient with

A patient with systemic

sclerosis and digital ulcers

Case - background

• 38 yo white female

• Disease duration: 15 years from first non Raynaud symptom

• ANA 1: 5120, anti-Scl-70 antibodies

• Diffuse skin fibrosis, mRSS 22/51, recently progressive (Rituximab)

• Organs:

- Mild ILD (CT Thorax < 10%, FVC 80%, DLCO 63%), echocardiography: unremarkable, NT-pro-BNP 183 (<130), Dyspnoea NYHA 1-2

- GI: Reflux, bloating

Case - Vascular manifestations

• Multiple Telangiectasia

• Puffy fingers

• Nailfold Capillaroscopy:

Case – Digital ulcers

Recurrent digital ulcers

2013

Case – Digital ulcers

Recurrent digital ulcers

2016

Case – Digital ulcers

Medication:

Bosentan 250 mg/d, Sildenafil 40 mg/d, Aspirin 100mg/d, Amlodipin 20 mg/d, Nitroglycerin Crème

2%, Ilomedin every 3 months 3 days

SSc 4 - 23

Prevalence of digital Ulcers (DU) Pittsburgh- and Royal-Free-Hospital-London- Database

*1/3 of all SSc-Patients with persistent DU(= persistent or recurrent DU of at least 6 months)

All SSc-Patients(n = 2080)

SSc-Patients with DU (active or in the past)

58 %SSc-Patientswithout DU

42 %

SSc-Patients with DU(active or in the past)

30 %44 %

Persistent DU* 56 %

SeriousDU

Steen V et al. Rheumatol 2009;48:iii19-iii24

Number of ulcers per patient

Nihtyanova, Ann Rheum Dis 2008;67:120-3

Standardized treatment algorithm in Zurich

EULAR treatment

recommendations 2016

In press

Annals of the Rheumatic Diseases

Two RCTs indicate that intravenous iloprost is efficacious in healing digital ulcers in patients

with SSc.

Intravenous iloprost should be considered in the treatment of digital ulcers in patients with SSc.

Intravenous iloprost should be considered in particular in SSc patients with DUs not responding to oral therapy

SSc 4 - 28

Iloprost i. v.*Randomized placebo controlled studies for DU in SSc-

Patients

Author Disease n Medication Result

Wigley et

al. 1992

Secondary RP

in SSc-Patients

with DU (n =

11)

35 Iloprost (0,5–2,0 ng/kg/min)

or Placebo 6 h i. v. on 5

consecutive days

After 10 Weeks.: Healing of all

ulcers in 6 / 7 Patients

Wigley et

al. 1994

Secondary RP

in SSc-Patients

with DU (n =

73)

131 Iloprost i. v. (0,5–

2,0 ng/kg/min) or Placebo

over 6 h on 5 consecutive

days

After 3 weeks: Healing of lesions

≥ 50 % in 14,6 % more Iloprost-

than Placebo-Patients;

New DU after 9 weeks:

in 25 % with Iloprost

32,8 % with Placebo (p > 0,2)

Kawald et

al. 2008

Secondary RP

in SSc-Patients

with DU (n =

37)

50 Iloprost i. v. max. tolerated

dose (up to 2 ng/kg/min) or

low dose (0,5 ng/kg/min)

over 6 h daily. for 21 days

Both doses:

Reduction of DU by 80 %

A A meta-analysis of 3 RCTs and results of an independent RCT indicate that PDE-5

inhibitors improve healing of digital ulcers in patients with SSc.

Moreover, the results of one small RCT indicate that PDE-5 inhibitors may prevent development of new digital ulcers in SSc.

PDE-5 inhibitors should be considered in the treatment of digital ulcers in SSc patients.

SSc 4 - 30

PDE-5-Inhibitors*RCTs for DU in SSc

Author Disease n Medication Result

Fries et

al. 2005

Prim. RP (n = 2)

Sek. RP (n = 16)

with DU (n = 6)

18 Sildenafil 2 × 50

mg/d over 4

weeks or Placebo;

after 1 week

Wash-out &

Cross-over

Beginnning DU-Healing

in 6 / 6 Patients,

complete healing in 2/6

Patients

Shenoy et

al. 2010

SSc-Patients,

with DU (n = 7)

25 Tadalafil 1 × 20

mg/d over 6

weeks or Placebo;

after 1 week

Wash-out

Healing of all digital

ulcers vs. 3/13 in the

Placebo group

Seduce trial (Sildenafil 20 mg x 3/d)

Primary endpoint (time to healing) not met

Hachulla et al, Ann Rheum Dis. 2016 Jun;75(6):1009-15

Bosentan has confirmed efficacy in two high-quality RCTs to reduce the number of

new digital ulcers in SSc patients.

Bosentan should be considered for reduction of the number of new digital

ulcers in SSc, especially in patients with multiple digital ulcers despite use of

calcium channel blockers, PDE-5 inhibitors or iloprost therapy.

0

10

20

30

40

50

60

70

80

90

100

≥1 ≥4 ≥7 ≥10

Number of new ulcers (n)

Pati

en

ts w

ith

no

r m

ore

ulc

ers

(%

)

0

10

20

30

40

50

60

70

80

90

100

≥1 ≥4 ≥7 ≥10

Number of new ulcers (n)

All patients (ITT) All patients w ith baseline DU (ITT)

Placebo

Bosentan

RAPIDS-1: Patients with new DUs over 16

weeks

Korn JH, et al. Arthrit is Rheum 2004;50:3985-93.

Ulzera in SSc patients:

No Vasculitis, but Vaskulopathy

Carulli et al, Arthritis Rheum 2005, 52:3772-82

Perivascular inflammation Small arteries

Platelet activation

Case – Digital ulcers

Medication:

Bosentan 250 mg/d, Sildenafil 40 mg/d, Aspirin 100mg/d, Amlodipin 20 mg/d, Nitroglycerin Crème

2%, Ilomedin every 3 months 3 days

Case – Digital ulcers

Progression of ulcers, necrosis

Botulinum toxin for the treatment of digital ulcers

Evidence for botulinum toxin in the treatment

of Raynaud/digital ulcers

Żebryk P et al, Arch Med Sci. 2016 Aug 1;12(4):864-70.

Case – Digital ulcers

Amputation necessary, all other ulcers healed

Case – Digital ulcers

Recurrence of ulcers 3 months after last Botox injection

Autologous adipose-derived stromal

vascular fraction for digital ulcers in SSc?

Granel et al, Ann Rheum Dis. 2015 Dec;74(12):2175-82

12 patients, uncontrolled, baseline 15 ulcers, 6 months: 7 ulcers

26.01.2017 42|

Acknowledgments

Center of Experimental Rheumatology

Department of Rheumatology,

University Hospital Zurich

Oliver Distler

Britta Maurer

Gabriela Kania

Astrid Jüngel

Florian Renoux

Janine Schniering

Mara Stellato

Anastasiia Kozlova

Michal Rudnik

Zhongning Guo

Masaya Yokota

Li Guo

Miki Takata

Rucsandra Dobrota

Matthias Brunner

Mike Becker

Caroline Ospelt

Kerstin Klein

Mojca Frank-Bertoncelj

Michel Neidhart

Emmanuel Karouzakis

Agnieszka Pajak

Peter Künzler

Maria Comazzi

Bea Henriques

Dominic Thorley

University Hospital Zurich

University of Zurich

Department of Internal Medicine,

University of Texas Houston

Shervin Assassi

Gloria A. Salazar

Department of Pulmonology,

University Hospital Zurich

Matthias Brock

Department of Rheumatology,

Leiden University Medical Center

Fina Kurreeman

Jeska de Vries-Bouwstra

Tobias Messemaker

Division of Rheumatology&Immunology

Medical University of South Carolina

Carol Feghali-Bostwick

Department of Internal Medicine 3,

Rheumatology and Immunology,

Friedrich-Alexander University

Erlangen-Nuremberg

Jörg HW Distler