U N I V E R S I T Ä T S M E D I Z I N B E R L I N

Transcription

1 U N I V E R S I T Ä T S M E D I Z I N B E R L I N

2 Chronic Urticaria: the role of mast cells and basophils Marcus Maurer Allergie-Centrum-Charité Department of Dermatology and Allergy Charité - Universitätsmedizin Berlin

3 What is the role of mast cells?

4 Mast cells are allergy cells Allergen Allergy MC

5 IL-3R, IL-4R, IL-6R,IL-10R, IL-15R C3aR, C5aR, CR1/2, CR3, CR4 CXCR1, 2, 4, CCR3, 5 PAR2, OTRs, A 3 R TrkA, MC-1/MC-5 PIR-A/PIR-B FcεRI, Fc RIIb, Fc RIII TLR1, 2, 3, 4, 6, 7, 8, 9 EP-1/EP-3, CysLT1R c-kit, CD48, LTβR ET A /ET B, upar CB1/CB2, VR CD40L, OX40 GITR, B7-1, -2 TSLP, IL-25, IL-33 NK1R

6 Serotonine, Heparin, Histamine, Chondroitinsulfate Chymase, Tryptase, Carboxypeptidase A, Cathepsin G Prostaglandins, Leukotrienes, Platelet-activating Factor IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-8, IL-9, IL-10, IL-11, IL-12, IL- 13, IL-14, IL-15, IL-16, IL-17, IL-18, IL-21, TNF, IFNγ, GM-CSF, TGF-β, bfgf, VPF/VEGF, NGF, MIP-1α, MCP-1, RANTES, IP-10, TSLP, IL-25, IL-33,

7 Mast cells / mm 2 skin Normal Distribution of Skin Mast Cells Head 60 Hands/Feet Trunk Arms/Legs Body regions Weber et al., Br J Dermatol 2003; 148: 224

8 Mast cells / mm 2 skin Normal Distribution of Skin Mast Cells 80 Head Hands/Feet 60 Arms/Legs 40 Trunk 20 0 Epidermis Skin layers Subcutis Weber et al., Br J Dermatol 2003; 148: 224

9 Can t live with them, Can t live without them Innate Immunity Bacteria Allergen Allergy MC Adaptive Immunity Parasite

10 What is their role in chronic urticaria? Innate Immunity Bacteria Allergen Allergy MC Adaptive Immunity Parasite

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12 The pathophysiology of CSU PRURITUS ERYTHEMA WHEAL INFILTRATE

13 The pathophysiology of CSU Activation PRURITUS Vasodilation ERYTHEMA Extravasation WHEAL Recruitment INFILTRATE

14 The pathophysiology of CSU IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-8, IL-10, IL-13, TNF, MIPs, IFN-, GM-CSF, TGF-b, bfgf, VPF/VEGF, PGD 2, LTB 4, LTC 4, PAF, histamine, serotonine, heparin, chondroitinsulfate, chymase, tryptase, CPA Activation Vasodilation Extravasation Recruitment PRURITUS ERYTHEMA WHEAL INFILTRATE

15 The pathophysiology of CSU MC IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-8, IL-10, IL-13, TNF, MIPs, IFN-, GM-CSF, TGF-b, bfgf, VPF/VEGF, PGD 2, LTB 4, LTC 4, PAF, histamine, serotonine, heparin, chondroitinsulfate, chymase, tryptase, CPA Activation Vasodilation Extravasation Recruitment PRURITUS ERYTHEMA WHEAL INFILTRATE

16 The pathophysiology of CSU IgE /anti-ige/antifceri SCF IgG LPS Complement Anaphylatoxins Neuropeptides Endothelin-1 Bacteria Interleukins Chemokines Oxytocine Leukotriene POMCs Prostaglandins Cannabinoids Adenosine Urokinase Capsaicin? FceRI Kit Fc R TLRs CR1/2, CR3 C3aR, C5aR NK1 ET A /ET B CD48 IL-3,4,15R CCR3 OTRs CysLT1R MC-1/MC5 EP1/EP3 CB1/CB2 A2b/A3 MC upar VR PIRA/PIRB IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-8, IL-10, IL-13, TNF, MIPs, IFN-, GM-CSF, TGF-b, bfgf, VPF/VEGF, PGD 2, LTB 4, LTC 4, PAF, histamine, serotonine, heparin, chondroitinsulfate, chymase, tryptase, CPA Activation Vasodilation Extravasation Recruitment PRURITUS ERYTHEMA WHEAL INFILTRATE

17 The pathophysiology of CSU C A U S E IgE /anti-ige/antifceri SCF IgG LPS Complement Anaphylatoxins Neuropeptides Endothelin-1 Bacteria Interleukins Chemokines Oxytocine Leukotriene POMCs Prostaglandins Cannabinoids Adenosine Urokinase Capsaicin? FceRI Kit Fc R TLRs CR1/2, CR3 C3aR, C5aR NK1 ET A /ET B CD48 IL-3,4,15R CCR3 OTRs CysLT1R MC-1/MC5 EP1/EP3 CB1/CB2 A2b/A3 MC upar VR PIRA/PIRB IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-8, IL-10, IL-13, TNF, MIPs, IFN-, GM-CSF, TGF-b, bfgf, VPF/VEGF, PGD 2, LTB 4, LTC 4, PAF, histamine, serotonine, heparin, chondroitinsulfate, chymase, tryptase, CPA Activation Vasodilation Extravasation Recruitment PRURITUS ERYTHEMA WHEAL INFILTRATE

18 Chronic urticaria is not an allergy! < 1% relevant sensitizations Chronic Spontaneous Urticaria

19 Chronic urticaria is not an allergy! < 1% relevant sensitizations 0% relevant sensitizations Chronic Spontaneous Urticaria Chronic Inducible Urticaria

20 High total IgE (%) Total IgE levels are increased in CSU * CSU Patients Healthy Controls Staubach,, Maurer, Mycoses 2008: 52;

21 Is IgE involved in the pathogenesis of chronic urticaria?

22 Capture ELISA for IgE-anti-TPO Detection biot. biot. Strept.Av-AP Biotinylated TPO IgE-anti-TPO (Serum) Anti-human-IgE Altrichter et al., PLoS ONE 2011: 12; 6

23 IgE-anti-TPO (IU/ml) 25 n = CSU Altrichter et al., PLoS ONE 2011: 12; 6

24 IgE-anti-TPO (IU/ml) IgE-anti-TPO (IU/ml) n = 300 n = Healthy Controls 0 CSU Altrichter et al., PLoS ONE 2011: 12; 6

25 IgE-anti-TPO (IU/ml) IgE-anti-TPO (IU/ml) n = 300 n = Healthy Controls 0 CSU Altrichter,..., Maurer, PLoS ONE: 2011: 12; 6

26 IgE-anti-TPO in CSU Altrichter et al., PLoS ONE 2011: 12; 6

27 Patients without wheals (in %) Patients with Complete Disease Control (no more wheals ) Anti-IgE Placebo 0 Anti-IgE Placebo Maurer et al. J Allergy Clin Immunol 2011; 128:

28 Wheal Score Asteria II: Omalizumab works in CSU Treatment Week Placebo Omalizumab 75 mg Omalizumab 150 mg Omalizumab 300 mg Maurer et al., N. Engl. J. Med. 2013: 368;

29 X-ACT study: CSU patients with angioedema benefit from omalizumab Angioedema Activity Score (AAS) AE-QoL Total Score *** p = p = p = *** *** p = *** Follow Weeks up Baseline Baseline Follow Weeks up Omalizumab 300 mg Placebo Omalizumab 300 mg Placebo Staubach et al., Allergy 2016

30 Omalizumab for the treatment of CSU: A meta-analysis of randomized clinical trials Zhao et al. J. Allergy Clin. Immunol. 2016: in press

31 How is IgE involved in the pathogenesis of chronic urticaria?

32 The role of Fc ε RI and IgE in MC activation in CSU MC

33 The role of Fc ε RI and IgE in MC activation in CSU Fc e RI MC

34 The role of Fc ε RI and IgE in MC activation in CSU Fc e RI IgE MC

35 The role of Fc ε RI and IgE in MC activation in CSU Fc e RI IgE Allergen MC

36 The role of Fc ε RI and IgE in MC activation in CSU Fc e RI IgE Allergen MC Auto- Allergen Autoimmunity Type I

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38 The role of Fc ε RI and IgE in MC activation in CSU Fc e RI IgE Allergen MC Auto- Allergen Autoimmunity Type I

39 The role of type I autoimmunity ( autoallergy ) in the pathophysiology of CSU

40 The role of type I autoimmunity ( autoallergy ) in the pathophysiology of CSU CSU patients often have IgE-anti-thyreoperoxidase (TPO) IgE-anti-TPO+ CSU patients benefit from omalizumab IgE-anti-TPO & TPO degranulates mast cells

41 Autoallergic Mast Cell Degranulation in CSU Shin et al., J. Korean Med. Sci. 2015; 30: 705-9

42 The role of type I autoimmunity ( autoallergy ) in the pathophysiology of CSU CSU patients often have IgE-anti-thyreoperoxidase (TPO) IgE-anti-TPO+ CSU patients benefit from omalizumab IgE-anti-TPO & TPO degranulates mast cells CSU patients often have IgE-anti-DNA CSU patients have IgE against >200 autoantigens

43 Ig E (U /m l) Most of the IgE reactivity in CSU patients is directed against self to ta l Ig E to ta l a u to Ig E CSU Patients C S U p a tie n ts Control Subjects c o n tro l s u b je c ts

44 The role of type I autoimmunity ( autoallergy ) in the pathophysiology of CSU CSU patients often have IgE-anti-thyreoperoxidase (TPO) IgE-anti-TPO+ CSU patients benefit from omalizumab IgE-anti-TPO & TPO degranulates mast cells CSU patients often have IgE-anti-DNA CSU patients have IgE against >200 autoantigens Most of the IgE reactivity in CSU patients is against self

45 IgE-anti-TPO+ CSU patients have higher total IgE Shin et al., J. Korean Med. Sci. 2015; 30: 705-9

46 The role of type I autoimmunity ( autoallergy ) in the pathophysiology of CSU CSU patients often have IgE-anti-thyreoperoxidase (TPO) IgE-anti-TPO+ CSU patients benefit from omalizumab IgE-anti-TPO & TPO degranulates mast cells CSU patients often have IgE-anti-DNA CSU patients have IgE against >200 autoantigens Most of the IgE reactivity in CSU patients is against self CSU patients have elevated total IgE

47 The role of Fc ε RI and IgE in MC activation in CSU Fc e RI IgE Allergen MC Auto- Allergen Autoimmunity Type I

48 The role of Fc ε RI and IgE in MC activation in CSU Fc e RI IgE Allergen MC IgG-anti-Fc e RI Auto- Allergen Autoimmunity Type II IgG-anti-IgE Autoimmunity Type I

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50 The role of Fc ε RI and IgE in MC activation in CSU Fc e RI IgE Allergen MC IgG-anti-Fc e RI Auto- Allergen Autoimmunity Type II IgG-anti-IgE Autoimmunity Type I

51 The role of type II autoimmunity in the pathophysiology of CSU Some CSU patients have IgG-anti-FceRI The serum of some CSU patients activates Basos / MCs Some CSU patients are ASST+ ASST+ patients are different from ASST- patients

52 The role of type II autoimmunity in the pathophysiology of CSU ELISA for IgG-anti-Fc ε RI Detection of presence of Fc ε RI

53 The role of type II autoimmunity in the pathophysiology of CSU Basophil Activation Test (BAT) Detection of direct activation of Basos/MCs by serum components ELISA for IgG-anti-Fc ε RI Detection of presence of Fc ε RI

54 The role of type II autoimmunity in the pathophysiology of CSU Autologous Serum Skin Test (ASST) Detection of autoreactivity Screening for type II autoimmunity Basophil Activation Test (BAT) Detection of direct activation of Basos/MCs by serum components ELISA for IgG-anti-Fc ε RI Detection of presence of Fc ε RI

55 Autologous Serum Skin Test (ASST)

56 Autoreactive Urticaria Serum Serum 1:1 Histamine Vehicle Autologous Serum Skin Test

57 The role of Fc ε RI and IgE in MC activation in CSU Fc e RI IgE Allergen MC IgG-anti-Fc e RI Auto- Allergen Autoimmunity Type II IgG-anti-IgE Autoimmunity Type I

58 Are type I autoimmune ( autoallergic ) CSU patients different from type II autoimmunity CSU patients?

59 Both, type I and II autoimmune CSU patients should respond to omalizumab.

60 The role of Fc ε RI and IgE in MC activation in CSU Fc e RI IgE Allergen MC IgG-anti-Fc e RI Auto- Allergen Autoimmunity Type II IgG-anti-IgE Autoimmunity Type I

61 The role of Fc ε RI and IgE in MC activation in CSU Fc e RI Allergen MC IgG-anti-Fc e RI Auto- Allergen Autoimmunity Type II IgG-anti-IgE Autoimmunity Type I

62 The role of Fc ε RI and IgE in MC activation in CSU Allergen MC IgG-anti-Fc e RI Auto- Allergen Autoimmunity Type II IgG-anti-IgE Autoimmunity Type I

63 Both, type I and II autoimmune CSU patients should respond to omalizumab. But: This should take longer in type II autoimmune CSU.

64 Complete responders (%) Time to response to omalizumab in CSU Days after first injection of omalizumab Gericke et al., JACI 2016, in press

65 Omalizumab responders (%) Type II autoimmune CSU patients take longer to respond to omalizumab P < BAT-negative BAT-positive Days after first injection of omalizumab Gericke et al., JACI 2016, in press

66 Omalizumab responders (%) Time to response (days) Type II autoimmune CSU patients take longer to respond to omalizumab P < P < 0.05 BAT-negative BAT-positive Days after first injection of omalizumab 0 BAT positive BAT negative Gericke et al., JACI 2016, in press

67 BAT Histamine release (%) Type II autoimmune CSU patients take longer to respond to omalizumab 100 P < > 8 Days after omalizumab injection positive neg. Gericke et al., JACI 2016, in press

68 Omalizumab responders (%) Type II autoimmune CSU patients take longer to respond to omalizumab Time to response (days) P < P < 0.05 ASST-negative ASST-positive Days after first injection of omalizumab 0 ASST positive ASST negative Gericke et al., JACI 2016, in press

69 Fc ε RI+ cells (Change from Baseline) Omalizumab reduces dermal Fc ε RI+ cells in CSU 10 Placebo Omalizumab 300 mg 5 P = Day 140

70 UAS7 6 at Week 24 The response to omalizumab is fast or slow 0 24 Weeks 0 24 Weeks Omalizumab 300mg n=81 SORTING BY onset of response Response requires 2-5 Injections n=28 Response after 1 st Injection n=27

71 The role of Fc ε RI and IgE in MC activation in CSU Fc e RI IgE Allergen MC IgG-anti-Fc e RI Auto- Allergen Autoimmunity Type II IgG-anti-IgE Autoimmunity Type I

72 The role of Fc ε RI and IgE in MC activation in CSU Fc e RI IgE Allergen MC IgG-anti-Fc e RI Auto- Allergen Autoimmunity Type II IgG-anti-IgE Autoimmunity Type I

73 Can t live with them, Can t live without them Innate Immunity Bacteria Allergen Allergy MC Anti-Fc e RI Adaptive Immunity Parasite Anti-IgE Autoantigen Autoimmunity Autoallergy

74 Come and join us!

75 8 th International EMBRN Meeting Prague, May 25-27,

76 Division of of Dermatological Allergology Director of the Department of Dermatology and Allergy of Charité Universitätsmedizin Berlin: Professor. Dr. med. Dr. h.c. Torsten Zuberbier

77 Studies vs. Real Life Table 2. Types of urticaria and numbers of cases showing responsiveness to omalizumab Type of Urticaria Number of Cases Complete Response Significant improvement No significant improvement Chronic spontaneous urticaria (83 %) 3 (10 %) 2 (7 %) Inducible urticaria (71 %) 4 (12 %) 6 (17 %) - Cholinergic urticaria 8 5 (62 %) Delayed pressure urticaria 8 7 (88 %) Symptomatic dermographism 7 6 (86 %) Cold urticaria 6 3 (50 %) Solar urticaria 4 3 (75 %) Heat urticaria 1 - (0 %) - 1 Total (76 %) 7 (11 %) 8 (13 %) This table contains the responsiveness to omalizumab of 51 patients, 11 of whom presented With two and 1with three types of urticaria. Complete response indicates 90 % response, Significant improvement % improvement and no significant improvement < 30 % Response. Complete response: 90 % response; significant improvement: % improvement; no significant improvement: < 30 % response. Metz,, Maurer, J. Derm. Sci. 2013

78 Patients with complete response Studies vs. Real Life Initial Dose Second Dose % 76% 86% 90% 95% 95% 95% 12 57% Weeks of treatment Dose of omalizumab: 150 mg 225 mg 300 mg Updosing 150 mg 300 mg Metz,, Maurer, J. Derm. Sci. 2013

79 UAS score Studies vs. Real Life Omalizumab dose 150 mg 225 mg 300 mg Days Patients who became symptom-free during the first week after start of treatment (n=12) Metz,, Maurer, J. Derm. Sci. 2013

80 Studies vs. Real Life Table 2. Types of urticaria and numbers of cases showing responsiveness to omalizumab Type of Urticaria Number of Cases Complete Response Significant improvement No significant improvement Chronic spontaneous urticaria (83 %) 3 (10 %) 2 (7 %) Inducible urticaria (71 %) 4 (12 %) 6 (17 %) - Cholinergic urticaria 8 5 (62 %) Delayed pressure urticaria 8 7 (88 %) Symptomatic dermographism 7 6 (86 %) Cold urticaria 6 3 (50 %) Solar urticaria 4 3 (75 %) Heat urticaria 1 - (0 %) - 1 Total (76 %) 7 (11 %) 8 (13 %) This table contains the responsiveness to omalizumab of 51 patients, 11 of whom presented Omalizumab is not indicated for chronic inducible urticaria With two and 1with three types of urticaria. Complete response indicates 90 % response, Significant improvement % improvement and no significant improvement < 30 % Response. Complete response: 90 % response; significant improvement: % improvement; no significant improvement: < 30 % response. Metz,, Maurer, J. Derm. Sci. 2013, in press

81 Change in CFTs (FricTest) CFTs (Stufen) Omalizumab works in Symptomatic Dermographism 0 Omalizumab Placebo 150 mg 300 mg * ** 1 0 Placebo 150 mg Omalizumab 300 mg Omalizumab Woche Omalizumab-Injektionen Primärer Endpunkt Maurer et al., manuscript in preparation

82 Critical friction thresholds (FricTest ) Omalizumab works in Symptomatic Dermographism Placebo 150 mg Omalizumab 300 mg Omalizumab Baseline Week 10 Baseline Week 10 Baseline Week 10 Metz et al., manuscript in preparation

83 MC IgE Omalizumab IgG-anti-IgE Autoallergen FceRI non-fceri-receptors Hours Days Weeks

84 MC IgE Omalizumab IgG-anti-IgE Autoallergen FceRI non-fceri-receptors Hours Days Weeks

85 MC IgE Omalizumab IgG-anti-IgE Autoallergen FceRI non-fceri-receptors Hours Days Weeks

86 MC MC IgE Omalizumab IgG-anti-IgE Autoallergen FceRI non-fceri-receptors Hours Days Weeks

87 MC MC IgE Omalizumab IgG-anti-IgE Autoallergen FceRI non-fceri-receptors Hours Days Weeks

88 MC MC MC IgE Omalizumab IgG-anti-IgE Autoallergen FceRI non-fceri-receptors Hours Days Weeks