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

Asthma Author Popolazione Incidence (10 6 ab./year) Watts et al. General Population 2.4-3.7 Polyposis Kurland et al. General Population 4 Diagnostic Criteria Eosinophilia >10% American College of Reid et al. General Population 3.3 ≥ 4 criteria Rheumatology (1990) Specifity: 99.7% Pulmonary Martin et al. General Population 6.8 Sensitivity: 85% infiltrates Non asthmatics 1.8 Asthmatics 64.4 Neuropathy Wechsler/Drazen Asthmatics (anti-R-CysLTs therapy) 56-74 Positive biopsy for vasculitis

High Eosinophils Churg-Strauss High eosinophilic non allergic (nasal polyps) Low IgE High IgE Low Eosinophils Matucci A., Vultaggio A, et al. SIAIC-SIS, Terrasini, 2009

Asthma as starting condition for Churg-Strauss Syndrome PHASE 3 PHASE 1 PHASE 2 (VASCULITIS) (ASTHMA/ATOPY) (IPEREOSINOPH.) Severe Overt disease with persistent Astma multiple organ involvement

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 - PERIPHERAL BLOOD TISSUES LIMPH NODE Tissue Vasculites IL-25 Infiltration CD95s CD95s CD95 v CD95 V EOTAXIN IL-5 Th2 E GM-CSF Ag ? CD69 Eotaxins, MCP-3/4 (CCR3); APC Y Y B MDC/TARC (CCR4) IL-4 Y Y Y IL-5 M (ANCA) E Th1/ IL2; IL-17; IFN- γ M E Th17 E M M E E TNF- α M «Type 2» granuloma

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

Treatment of Churg-Strauss Syndrome “Multicenter French Vasculitis Study Group” 100% R 93% E 35% M I 80% Asthma S 50% S I O N 1 yr 5 yrs T H E R A P Y - Ribi C., et al. Arthritis Rheum 2008;58:586-94 - Guillevin L., et al. Arthritis Rheum 2003;49:93-100

The Era of Biological Treatment And Our experience

Phenotypes/Endotypes of CSS Clinical Phenotypes Asthma Heart Gastroent. SNC/SNP Skin Kidney ANCA+ ANCA- Endotypes IL-5 Eotaxins TNF- α ?

CHURG-STRAUSS SYNDROME (CASE SERIES) Asthma Nasal Skin ANCA+ Chest Atopy Pheripheral Kidney Joints polyps Neural S. 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 Matucci A,Vultaggio A., et al. (unpublished data)

Asthma patients Churg-Strauss patients Severe Asthma patients SNC Heart Kidney Joints SNP - High dose of steroids (pulse) - Immunosoppressor (CKF) 79 Patients with CSS patients No Responder patients (10,3%) - Inhalant steroids 8 - High dose of oral steroids - Immunosoppressor (CoA, MTX, AZA) 71 Responder patients Matucci A, et al. (unpublished data)

Clinical and laboratory findings Patients Gender/Age Organ involvement Disease Previous duration 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 Patients Atopy/total ANCA Eosinophils ECP IgE (kU/l) status % - a.v. 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 Non responders sTNF- α Patients IL-6 IL-10 (pg/ml) (pg/ml) (pg/ml) 6/8; 75% 1 CF 8 14 160 549 2 SV 19 74 3 BE* 6 5 220 High sTNF- α 4 CG 9 17 257 5 GM 7 15 434 P=0.006 6 LM Nd Nd Responders Nd 2/15; 13% ------------ -------------- Mean ± 9.8 ± 2.3 25 ± 12.4 324 ± 72.6 SE Soggetti sani Soggetti in shock Controllo (n=10) Settico (n=10) 13.8 ± 4.5 207.7 ± 58.7 Personal unpublished data

Serum Eotaxin levels in Churg-Strauss patients after Infliximab therapy 300 P=0.15 250 200 Eotaxin 150 pg/ml 100 50 0 01/01/1900 02/01/1900 Pre-therapy Post-therapy 600 500 E otaxin pg/m l 400 300 200 100 0 1 2 Pre-therapy Post-Therapy Personal unpublished data

et al.

Clinical response to IFX p = 0.05 p = 0.01 20 Asthma control test Asthma control test 25 p = 0.01 15 CF 20 score SV 10 15 BE CG 10 5 GM 5 LM 0 0 baseline therapy baseline during therapy 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 CKF 1g Mepolizumab 750 mg Mepolizumab 750 mg Kahn JE, et al. J All Clin Immunol 125;1:267-270

Mepolizumab in EGPA (personal data) Patients (disease) N* Eos Pre (%, VA) Eos post (%, VA) somministrazioni 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)

Mepolizumab in EGPA (personal data) FEV1 ACT OCS OCS Patients (disease) FEV1 Pre ACT pre post post (mg) (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

121 CHURG-STRAUSS PATIENTS 41 ANCA + 80 ANCA - 36 (87,7%) PERIPH. 39 (48,7%) PERIPH. P<0.005 NERVOUS SYST. + NERVOUS SYST. + 6 (7,5%) KIDNEY + 9 (22%) KIDNEY + P<0.05 Matucci A,Vultaggio A., et al. (unpublished data)

Rituximab treatment in CSS with Pulmonary and Peripheral Nervous System Involvement 2500 2000 Eosinophils cell/mm3 1500 1000 500 0 1 2 Pre-Rituximab Pre-Rituximab (7 infusions)

Conclusions • Asthma with high eosinophilia is a risk condition for CSS (EGPA) • Sytemic steroids remain the mainstay of therapy of 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) University of Florence, Italy Careggi Hospital Laura Dies Francesca Nencini Alessandra Vultaggio Sara Pratesi Oliviero Rossi Daniele Cammelli