Clinical spectrum and therapeutic approach in pemphigus vulgaris

Transcription

1 Clinical spectrum and therapeutic approach in pemphigus vulgaris Michael Hertl Department of Dermatology and Allergology Philipps University, Marburg, Germany F125: Bullous Diseases: Diagnostic and Management Algorithm, AAD, Orlando, Vancouver, March 6, 2017

2 DISCLOSURE OF RELEVANT RELATIONSHIPS WITH INDUSTRY Consulting: GSK, UCB, Biogen IDEC, Almirall, Roche Grants: Fresenius, Biotest, TOPAS Immunotherapeutics Honoraria: Fresenius, Janssen Cilag, Abbvie

3 Pemphigus Hertl et al. J Clin Invest, 2006

4 Diagnostic Algorithm History! Histopathology Direct Immunofluorescence Indirect Immunofluorescence Level of split formation Tissue-bound autoantibodies Serum autoantibodies Diagnosis ELISA Immunoblot Immunoprecipitation

5 Pemphigus First line: Systemic corticosteroids, i.e. prednisolone 0,5 1,5 mg/kg/d Second line: Adjuvant immunosuppressives (azathioprine, mycophenolate, cyclophosphamide) Third line: Rituximab, immunoadsorption, intravenous immunglobulins Supportive measures: Antiseptics, intradermal corticosteroids etc. EDF/EADV Guidelines: Hertl et al, JEADV 2015; Murrell et al, in press; Joly et al, in press

6 Targeted therapy of pemphigus Immunoadsorption

7 RCT Efficacy and Safety of Adjuvant Immunoadsorption in Pemphigus (25 German Centers) Study arm newly diagnosed relapsed chronic refractory total BMT + IA BMT total Eming et al, in preparation

8 Explorative data analysis Primary endpoint time until clinical remission ITT- total population ITT-subgroup analysis high disease severity BMT BMT BMT+IA BMT+IA HR: 1.350; 95%CI: HR: 2.052; CI95%:

9 Explorative data analysis Secondary endpoint cumulative prednisolone dose Study arm n n miss min q1 median q3 max BMT+IA BMT Wilcoxon-Mann-Whitney-Test: p=0.0330

10 Targetted therapy of pemphigus Intravenous Immunoglobulins (IVIG)

11 . A randomized double-blind trial of intravenous immunoglobulin for pemphigus. Amagai M et al. J Am Acad Dermatol. 2009;60(4): of steroid refractory PV or PF (unresponsive to low prednisone dose, < 20mg/d) single cycle of IVIG (400 mg/d for 5 days) vs single cycle of IVIG (200 mg/d for 5 days) vs Placebo Time to escape: time until the initial prednisone dose (20 mg/d) was considered to be ineffective and had to be increased Outcome: time to escape was longer in patients treated with 400 mg/d of IVIG (but not with 200mg) than in the placebo group Follow up period : > 3 months

12 Intravenous immunoglobulins (IVIG) I.v. application over 2 5 days per cycle (2 g/kg/month) Adjuvant setting (combined with systemic glucocoticoids and immunosuppressive adjuvants Case reports, case series, including juvenile pemphigus Caveat: Headache, nausea Aseptic meningitis is rare but significant (patient history for migraine) Absolute IgA deficiency

13 Targeted therapy of pemphigus Anti-CD20

14 Prospective trials on the efficacy of rituximab in pemphigus Clinical remission: 81% Ahmed et al (NEJM 2007, Rtx + IVIG, n 11) 86% Joly et al (NEJM 2007, Rtx +/ glucocorticoids, n 21) Median duration until CR: 63 d vs 68 d (Ahmed vs Joly) Relapse rates: 2/11 (20 %) 12 mo (Ahmed et al) 7/21 (33 %) 24 mo (Joly et al)

15 Longterm remission of refractary pemphigus on rituximab (Ahmed et al., NEJM 2007, n-10) Ahmed et al, NEJM 2015

16 Longterm efficacy of rituximab Colliou N et al Science Transl Med /3 patients never relapsed after one cycle of rituximab: > long lasting immunological effect (change in the B lymphocytes repertoire) 2/3 of patients relapsed during the 6 years after rituximab > 80% of relapsing patients who were re treated with rituximab achieved CR

17 Rituximab induction of Breg cells in remittent pemphigus Colliou et al Sci Transl Med 2013

18 Early treatment with rituximab leads to longterm remission of pemphigus Colliou N et al, Science Transl Med Lunardon L et al. Arch Dermatol 2012 Rate of CR off therapy: 100% rituximab as first line treatment 29% second or third line (p= 0.009). Patients who achieved CR after rituximab had been treated earlier in the course of the disease than patients who did not achieve CR (19 months vs 86 months ), (p = 0.01)

19 Rituximab doses Cianchini, G., et al. Jam Acad Dermatol, 2012 leschem Yaet al. J Am Acad Dermatol 2013 Heelan K et al. JAMA Dermatol 2014 Amber et al, JEADV 2015 The autoimmune regimen ( 2 x 1g) seems as effective as the oncology regimen 4 x 375 mg/m 2 body surface Two infusions of 500 mg seem less effective than 2 x 1g

20 Rituximab several modes of action Hertl et al. J Clin Invest 2006

21 Rituximab selectively inhibits autoreactive T cells in pemphigus Th1 IgG pre rituximab 1 month 3 months 6 months 12 months dsg3 specific Thcells / 10 5 PBMC TT specific Th1- cells / 10 5 PBMC anti-tt IgG [IU/ml] IgG anti-dsg3 IgG [PIV] 30 0 Th2 Th1 pre rituximab (n=11) 1 month (n=11) 3 months (n=11) 6 months (n=10) 12 months (n=8) 30 dsg3-specific T cell subsets [%] CD19 + B-cells [% of total lymphocytes] * ** Th1 Th2 B-cells Eming/Nagel et al, J Invest Dermatol 2008

22 Pemphigus T cell-based pathogenesis Dsg PKG Dsc Desmoglein Plakoglobin Desmocollin PKG Dsc3 Dsc3 Dsg3 Dsg3 Dsg3-Peptide HLA class II allele DRß1*0402/DOß1*0503 TCR Desmosome Epidermal keratinocyte Stratum corneum Epidermis Basal membrane zone Th2 IgG4 lgg1 IgE APC Tr1 APC Th1 B cell Th17 Tfh

23 Collaborations Luca Borradori, Berne Pascal Joly, Rouen Giovanna Zambruno, Rome Cassian Sitaru/Leena Bruckner-Tuderman, Freiburg Masayuki Amagai, Tokyo Takashi Hashimoto, Kurume Aimee Payne/ John Stanley, Philadelphia Claudio Feliciani, Parma Sergei Grando/ Kyle Amber, Irvine, USA Marcel Jonkman/Hendri Pas, Groningen Dedee Murrell, Sydney Marburg/Giessen Rüdiger Eming, MD Thomas Schmidt, PhD Christian Möbs, PhD Robert Pollmann, PhD Farzan Solimani, MD Verena Eubel, MD Hazem Juratli, MD Ansgar Schmidt, PhD Ritva Tikkanen, PhD FOR 2497