Andrea Matucci SOD Immunoallergologia AOU Careggi - Firenze - - PowerPoint PPT Presentation

Sindrome di Churg-Strauss (EGPA): Patogenesi, Terapia ed Esperienza Personale

Andrea Matucci

SOD Immunoallergologia AOU Careggi - Firenze andrea.matucci@unifi.it

XXXIII Congresso SIAAIC Toscana I Congresso SIAAIC Toscana-Emilia Romagna-S. Marino-Marche Convitto della Calza, Firenze 10-11 Novemre 2017

Specifity: 99.7% Sensitivity: 85%

Asthma Polyposis

Eosinophilia >10%

Pulmonary infiltrates

Neuropathy

Positive biopsy for vasculitis

Diagnostic Criteria American College of Rheumatology (1990)

≥ 4 criteria

Author Popolazione Incidence (106 ab./year)

Watts et al.

General Population 2.4-3.7

Kurland et al.

General Population 4

Reid et al.

General Population 3.3

Martin et al.

General Population Non asthmatics Asthmatics 6.8 1.8 64.4

Wechsler/Drazen

Asthmatics (anti-R-CysLTs therapy) 56-74

High eosinophilic non allergic (nasal polyps)

High Eosinophils Low Eosinophils High IgE Low IgE

Matucci A., Vultaggio A, et al. SIAIC-SIS, Terrasini, 2009

Churg-Strauss

Asthma as starting condition for Churg-Strauss Syndrome

PHASE 1 (ASTHMA/ATOPY) PHASE 2 (IPEREOSINOPH.) PHASE 3 (VASCULITIS)

Overt disease with multiple organ involvement Severe persistent Astma

Hystopathology of EGPA

a) Kidney b) Skin c) Intestine d e

a; b; c: (personal casistic) d; e: Greco et al. Autoimm. Rev 2015

CHURG-STRAUSS SYNDROME

• Pathogenic mechanisms -

APC

Th2

Th1/ Th17 M M M

IL-5 GM-CSF PERIPHERAL BLOOD TISSUES EOTAXIN

E

«Type 2» granuloma

IL2; IL-17; IFN-γ E E E E E

M

M vCD95

CD95s CD95

V

CD95s

Ag ? TNF-α

Vasculites Tissue Infiltration

IL-4 IL-5 LIMPH NODE

B

Y Y Y Y Y

(ANCA) CD69

Eotaxins, MCP-3/4 (CCR3); MDC/TARC (CCR4)

IL-25

Treatment Strategies before the Era of Biologicals

Five-Factors Score (FFS)

French Vasculitis Study Group 1 - Serum creatinine levels > 1,58 md/dl 2 - Proteinuria > 1 g/day 3 - Severe gastrointestinal tract involvement 4 - Cardiomiopaty 5 - Central nervous system involvement

FFS = 0 good prognosis FFS ≥ 2 increases the risk of mortality

Guillevin l, et al. Medicine (Baltimore) 1996;75:17-28

Therapeutic strategies of CSS

Acute phase

• Eos. Lung infiltration
• Eos. Kidney infiltration

SNC involvement

Treatment of CSS patients with FFS=0

• oral prednisone 1 mg/Kg for 3wks, tapering 5 mg every 10 days until withdrawal

in case of relapse add

• oral azathioprine 2/mg/Kg daily for 6 months or CKF 6 cycles (750mf/m2)

Treatment of CSS patients with FFS>1

• 3 consecutive 6-MPD pulses plus oral prednisone as above described plus CKF 12 cycles

(750mf/m2) plus oral azathioprine 2/mg/Kg daily for 1 year

50% 100%

93% 35%

1 yr 5 yrs

R E M I S S I O N T H E R A P Y

Treatment of Churg-Strauss Syndrome

“Multicenter French Vasculitis Study Group”

• Ribi C., et al. Arthritis Rheum 2008;58:586-94
• Guillevin L., et al. Arthritis Rheum 2003;49:93-100

80%

Asthma

The Era of Biological Treatment And Our experience

Phenotypes/Endotypes of CSS

Gastroent. Asthma

Heart SNC/SNP

Kidney

Clinical Phenotypes

Skin

ANCA+ ANCA-

TNF-α IL-5 Eotaxins

Endotypes

?

121 Churg-Strauss patients(≥4 ARA criteria) M/F: 41/80; age at diagnosis 50,1 ± 13,4 yrs History of Asthma: 9,2 yrs (3-25 yrs)

• Pheriph. Eosinophils at diagnosis: 35.6 ± 14.3

CHURG-STRAUSS SYNDROME (CASE SERIES)

Asthma Nasal polyps Chest Atopy Pheripheral Neural S. Kidney Joints Skin ANCA+

Matucci A,Vultaggio A., et al. (unpublished data)

SNC Heart Kidney Joints SNP

Churg-Strauss patients

Severe Asthma patients Asthma patients

• High dose of steroids (pulse)
• Immunosoppressor (CKF)

Responder patients No Responder patients (10,3%)

79 Patients with CSS patients

71 8

• Inhalant steroids
• High dose of oral steroids
• Immunosoppressor

(CoA, MTX, AZA) Matucci A, et al. (unpublished data)

Patients Gender/Age Organ involvement Disease duration Previous treatments

1 CF F/71 Lung, SNP, Joint 6 yrs CCS, IVIG, CyA 2 SV F/26 Lung, Joint 3 yrs CCS, CyA, MTX 3 BE F/58 Lung, SNP 20 yrs CCS, AZA, CyA, 4 CG M/60 Lung, skin 2 yrs CCS, MMF, CyA, IVIG 5 GM M/65 Lung, skin, SNP 4 yrs CCS, CKF 6 LM M/46 Lung, skin 8 yrs CCS, CyA

Clinical and laboratory findings

Patients Atopy/total IgE (kU/l) ANCA status Eosinophils % - a.v. ECP

1 CF No/236 neg 23.5% - 1920 41.3 2 SV No/9.28 neg 21.9% - 2230 70 3 BE No/24.5 neg 32% - 3250 65.6 4 CG No/250 pos 61% - 11041 46.5 5 GM No/2971 pos 33% - 3630 31.7 6 LM No/224 neg 15.1% - 1490 119

Matucci A,Vultaggio A., et al. (unpublished data)

et al.

TNF-a serum levels Responder and Non- Responder patients to traditional therapy

6/8; 75%

P=0.006

High sTNF-α 2/15; 13%

Non responders Responders

Patients IL-6 (pg/ml) IL-10 (pg/ml) sTNF-α

(pg/ml) 1 CF 8 14 160 549 220 257 434 Nd 2 SV 19 74 3 BE* 6 5 4 CG 9 17 5 GM 7 15 6 LM Nd Nd

• Mean ±

SE 9.8 ± 2.3 25 ± 12.4 324 ± 72.6

Soggetti sani Controllo (n=10) 13.8 ± 4.5 Soggetti in shock Settico (n=10) 207.7 ± 58.7

Personal unpublished data

Serum Eotaxin levels in Churg-Strauss patients after Infliximab therapy

50 100 150 200 250 300 01/01/1900 02/01/1900 Pre-therapy Post-therapy Eotaxin pg/ml

P=0.15

100 200 300 400 500 600 1 2 Pre-therapy Post-Therapy

E otaxin pg/m l

Personal unpublished data

et al.

Clinical response to IFX

p = 0.01 p = 0.05

5 10 15 20 baseline therapy

p = 0.01

Asthma control test

5 10 15 20 25 baseline during therapy

CF SV BE CG GM LM

Asthma control test score

Matucci A, Vultaggio A. et al (unpublished data)

Characteristics of Eosinophils

Khoury P, et al. Nat Rev Rheumatol. 2014

Mepolizumab (anti-IL-5) in refractory Churg-Strauss Syndrome

Kahn JE, et al. J All Clin Immunol 125;1:267-270

Mepolizumab 750 mg

CKF 1g

Mepolizumab 750 mg

Mepolizumab in EGPA

(personal data)

Patients (disease) N* somministrazioni Eos Pre (%, VA) Eos post (%, VA)

• 1. DSR (SCS)

3 17.8% (1400) 0% (0)

• 2. SM (SCS)

2 1.5% (270) 1% (190)

• 3. TS (SCS)

44 38% (3400) 1% (80)

• 4. MS (SCS)

45 15.5% (1670) 1.1% (100)

• 5. DLF (SCS)

45 26% (2000) 0% (0)

• 6. QG (SCS)

>50 33% (4000) 2.6% (190)

• 7. PS (BA)

17 9.5% (930) 3,5% (230)

Patients (disease) FEV1 Pre FEV1 post ACT pre ACT post OCS (mg) OCS (mg)

• 1. DSR (SCG)

78% Not done 15 20 25 10

• 2. SM (SCG)

79% Not done 19 25 Boli ev 7.5

• 3. TS (SCS)

69% 111% 14 22 15 5

• 4. MS (SCS)

65% 74% 17 25 5 2.5

• 5. DLF (SCS)

41% 70% 10 24 20 10

• 6. PS (BA)

42.9% 76.7% 15 20 5 2.5

Mepolizumab in EGPA

(personal data)

121 CHURG-STRAUSS PATIENTS 41 ANCA + 80 ANCA -

36 (87,7%) PERIPH. NERVOUS SYST. + 39 (48,7%) PERIPH. NERVOUS SYST. + 9 (22%) KIDNEY + 6 (7,5%) KIDNEY +

P<0.005 P<0.05

Matucci A,Vultaggio A., et al. (unpublished data)

500 1000 1500 2000 2500 1 2

Eosinophils cell/mm3

Pre-Rituximab Pre-Rituximab (7 infusions)

Rituximab treatment in CSS with Pulmonary and Peripheral Nervous System Involvement

Conclusions

• Asthma with high eosinophilia is a risk condition

for CSS (EGPA)

• Sytemic steroids remain the mainstay of therapy
• f CSS and cyclophosphamide is added to

achieve remission in severe forms but……..

• Most patients failed to control the disease

despite “full-blown” therapy

• Subtypes (endotypes) of CSS may exist
• New therapies with biological agents could be

considered

Akwnoledgements

Immunology and Cellular Therapy (E. Maggi) Immunoallergology Unit (F. Almerigogna)

Alessandra Vultaggio Oliviero Rossi Daniele Cammelli

University of Florence, Italy Careggi Hospital

Laura Dies Francesca Nencini Sara Pratesi