Sistemik skleroz: patogenezden tedaviye. Dr. Süleyman Serdar Koca Fırat Üniversitesi Tıp Fakültesi

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1 Sistemik skleroz: patogenezden tedaviye Dr. Süleyman Serdar Koca Fırat Üniversitesi Tıp Fakültesi

2 Raynaud fenomeni ve komplikasyonları Deri tutulumu İç organ tutulumları; - Pulmoner fibroz ve PAH - Kardit, perikardiyal efüzyon - GÖRH ve GİS tutulumu - Renal kriz - Artrit, miyozit

3 Sistemik skleroz Sınırlı SSK Vasküler bazlı tedaviler Yaygın SSk Vasküler bazlı tedaviler İmmünsupresifler Anti-fibrotikler RF Preskleroderma Çok erken skleroderma Komplikasyonların tedavisi

4 SSk patogenez Sakkas LI, et al. Nature Clinical Practice Rheumatology (2006)

5 SSk B hücre Anti-CD20 Anti-CD19 Belimumab

6 Belimumab Belimumab for the Treatment of Diffuse Cutaneous SSc (NCT ) (MMF/Belimumab vs. MMF/plasebo) Gordon JK, et al. Arthritis Rheumatol. 2018

7 Anti-CD19

8 Rituksimab deri Lafyatis ve ark. Arth & Rehum 2009

9 Rituksimab deri 20 dcssc RTX: 1 gr/2 hafta ve 2 kür* 48.5±20.4 ay izlem Deri, pulmoner ve artrit üzerine etkiler Bazal 12. ay p Son kontrol p Deri skoru 22.4 ± ± 7.5 < ± 7.2 < Silvia L. Bosello, et al. Seminars in Arthritis and Rheumatism, 2015

10 Rituksimab deri Vaka serisi + literatür derlemesi 10 hasta (5 dcssc, 5 lcssc) DÜ (0/6) yanıt yok Artrit (7/8), hipermelanoz (7/7), kaşıntı (6/8), kalsinoz (3/6) iyileşme mrds (bazal vs. 6. ay, p) Toplam: 15.3 ± 11.5 vs. 11 ± 7.3; p = dcssc: 25 ± 4.3 vs ± 4.6; p =0.022 dcssc vs. lcssc? Dilia Giuggioli, et al. Autoimmunity Reviews, 2015

11 Rituksimab ile devam eden çalışmalar Çalışma No Başlık Hedefler NCT Rituximab in Systemic Sclerosis (RECOVER) NCT Rituximab for Treatment of Systemic Sclerosis-Associated Pulmonary Arterial Hypertension (SSc-PAH) NCT Rituximab Versus Cyclophosphamide in Connective Tissue Disease-ILD (RECITAL) Artrit, mrds ve pulmoner fibroz ikincil sonlanım noktası PAH FVC (48. hafta) clinicaltrials.gov

12 SSk patogenez Sakkas LI, et al. Nature Clinical Practice Rheumatology (2006)

13 Tosilizumab SSk çalışmaları NCT WA fassinate çalışması 48 hafta kör tedavi periyodu 48 hafta açık uzatma periyodu Bazal 24. hafta 48. hafta 96. hafta Toc 162 mg/hafta sc 1:1 R Toc 162 mg/hafta sc Plasebo Khanna D, et al Lancet Efficacy and Safety of Tocilizumab in Participants With SSc focussced çalışması - NCT

14 Tosilizumab fassinate mrds 24. hafta 48. hafta Plasebo (n=44) Tosilizumab (n=43) P Khanna D, et al Lancet

15 Tosilizumab fassinate FVC 24. hafta 48. hafta Plasebo (n=44) Tos. (n=43) 4.5 ( 7.0 ile 1.9) 0.7 ( 3.2 ile 1.8) 6.3 ( 8.9 ile 3.8) 2.6 ( 5.2 ile 0.1) Khanna D, et al Lancet

16 İmatinib AE with possible relation SAE Event % Event Oedema 80 Haematuria (hospitalisations) 7 (1) Nausea 73 Pneumonia 2 (2) Myalgias 67 C difficile infection 2 (1) CK elevation 43 Infected ulcer 2 (2) Fatigue 40 Death (pneumonia) 1 (1) Anaemia 27 Acute gastroenteritis 1 (1) Pyrosis 13 Acute myocardial infarction 1 (1) Vomiting 13 Anaemia blood transfusion 1 (1) Weight loss 13 Fall 1 (1) Headaches 13 Fluid overload 1 (1) Effusions 10 Rectal prolapse, haemorrhoidal bleed 1 (1) Events (patients) Hypocalcemia 7 Nephrolithiasis 1 (1) Dry skin 7 Partial small bowel obstruction 1 (1) Erectile dysfunction Generalised weakness 7 Light-headedness 7 Bleeding post renal biopsy (hospitalisation) 1 (1) 7 Tachyarrhythmia/cardiomyopathy 1 (1) Faz IIa çalışması 1. yıl verileri. Spiera RF, et al. Ann Rheum Dis. 2011;70(6):

17 İmatinib İlacı bırakma oranı yüksek, Yanıt yetersiz Faz III çalışma için uygun değil. Pope J, et al. Arthritis Rheum ;63: Baseline 6 months Imatinib Placebo Imatinib Placebo No. of patients enrolled 9 1 No. of patients completing the study 4 1 MRSS Mean Range No. with tendon friction rubs Global assessment, mean ± SD (0 100-mm VAS) Physician's 46 ± ± Patient's 73 ± ± HAQ, mean ± SD (range 0 3) 1.66 ± ± ESR, mean ± SD mm/hour 20 ± ± CRP, mean ± SD mg/dl 9 ± ±

18 Tki: nilotinib, nintedanib, dasatinib Nilotinib (Tasigna ) in the treatment of early diffuse systemic sclerosis: an openlabel, pilot clinical trial Gordon et al. Arthritis Research & Therapy 2015 Nilotinib (N=7) Bazal 6. ay 12. ay P (6 ay) P (12 ay) MRSS 26.9 ± ± ± FVC 77.4 ± ± ± NCT A Trial to Compare Nintedanib With Placebo for Patients With Scleroderma Related Lung Fibrosis (SENSCIS ). Faz 3: Çift kör, Randomize Plasebo kontrollü FVC (52 hafta) SSK-ILD Hasta alımı devam ediyor Martyanov V et al. Novel lung imaging biomarkers and skin gene expression subsetting in dasatinib treatment of systemic sclerosis-associated interstitial lung disease. PLoS One. 2017

19 SSk tedavisi gelecek Rituksimab, abatasept, tosilizumab Basiliksimab 1 Rilonasept 2 Dasatinib 3 BIBF1120 (nintedanib) 7 GC-1008 (fresolimumab antitgf-beta) 5 IVA337 (pan-ppar agonist) 4 LPA1 antagonisti Lenabasum (cannabinoid res2 agonisti) RESOLVE-1 SLS-III (MMF vs. MMF+pirfenidon) clinicaltrials.gov

20 Endojen kannabinoidler Birçok hücrelerce üretilen lipid molekülü Anandamid ve 2- arachidonoylglycerol en sık çalışılanlarıdır CB1 reseptör SSS; CB2 reseptörü ise inflamataur hücreler ve fibroblastda eskprese CB2 knockout fareler fibroza (deri, karaciğer, böbre) yatkın, CB2 agonisti deneysel fibrozu baskılar Servettaz A, et al. Am J Pathol. 2010

21 Lenabasum faz 2 çalışması (JBT-SSc-001) Deri skoru Plasebo Lenabasum P Kötüleşen, % Değişmeyen, % İyileşen, % Delta mrss; plasebo grubu: -1.2, lenabasum grubu: -5.1

22 Sonuç olarak, SSk patogenezindeki gizem halen tam olarak çözülebilmiş değil Sır fibroblastlarda olmalı Fibroblastik aktiviteyi etkileyen; IL-6, tirozin kinaz, PPAR, CB2 aracıları potansiyel tedavi hedefleridir

23 İlginiz ve sabrınız için teşekkürler

24 J Clin Rheumatol Dec;23(8): doi: /RHU Rituximab Experience in Patients With Long-standing Systemic Sclerosis-Associated Interstitial Lung Disease: A Series of 14 Patients. Sari A, Guven D, Armagan B, Erden A, Kalyoncu U, Karadag O, Apras Bilgen S, Ertenli I, Kiraz S, Akdogan A. Abstract OBJECTIVES: The objective of this study was to report the experience with rituximab treatment in a case series of patients with long-standing systemic sclerosis-associated interstitial lung disease (SSc-ILD). METHODS: We reviewed the charts of 197 SSc patients. Fourteen patients who received rituximab for SSc-ILD participated in this analysis. Pulmonary function tests, high-resolution thorax computed tomography and modified Rodnan skin scores were evaluated at baseline and end of the follow-up. RESULTS: Median age was 53.2 years (interquartile range, years), and median disease duration was 9.1 years (interquartile range, years). At the end of median follow-up (15 months), although the median forced vital capacity value increased compared with baseline, the change was not statistically significant (52.5 vs. 58.0, P = 0.065). Forced vital capacity was improved in 4 patients and stabilized in 10 patients. Highresolution computed tomography was stable in 7 patients and worsened in 3 patients. Modified Rodnan skin scores remained stable at the end of follow-up (8.0 vs. 6.0, P = 0.6). CONCLUSIONS: The improvement or stabilization of pulmonary disease was observed in most SSc patients with longer disease duration and worse pulmonary function. Rituximab might be useful in this patient group who is resistant to conventional immunosuppressive treatments. PMID: DOI: /RHU