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 Disclosure of Significant Relationships with Commercial Companies and Organizations Funding of Research by Deutsche Forschungsgemeinschaft (DFG), EU (FP7, COST), European Centre of Allergy Research Foundation (ECARF), Urticaria Network e.v. (UNEV), Bayer, Leo, Novartis, Riemser, Uriach. Speaker and/or Advisor for Almirall Hermal, Bayer, BioCryst, Dyax, FAES, Genentech, Leo, Merckle Recordati, Moxie, MSD, Novartis, Riemser, Sanofi Aventis, Shire, Takeda, UCB, and Uriach. 1 / 2016, for past five years

3 Exploring the Management of Urticaria: Discussion of Optimal Treatment Strategies Marcus Maurer Allergie-Centrum-Charité Department of Dermatology and Allergy Charité - Universitätsmedizin Berlin

4 Classification of urticarias Acute Urticaria: < 6 weeks Chronic Urticaria: > 6 weeks Zuberbier et al., Allergy 2014: 69;

5 Classification of chronic urticarias Spontaneous Urticaria Inducible Urticaria Zuberbier et al., Allergy 2014: 69;

6 Classification of chronic urticarias Spontaneous Urticaria Inducible Urticaria Due to known cause Due to unknown cause Symptomatic Dermographism Cold Contact Urticaria Solar Urticaria Delayed Pressure Urticaria Heat Contact Urticaria Vibratory Urticaria Contact Urticaria Aquagenic Urticaria Cholinergic Urticaria Exercise-induced Urticaria / Anaphylaxis Zuberbier et al., Allergy 2014: 69;

7 Classification of chronic urticarias Spontaneous Urticaria Due to known cause Due to unknown cause Inducible Urticaria Symptomatic Dermographism Cold Contact Urticaria Solar Urticaria Delayed Pressure Urticaria Heat Contact Urticaria Vibratory Urticaria Contact Urticaria Aquagenic Urticaria Cholinergic Urticaria Zuberbier et al., Allergy 2014: 69;

8 Chronic Inducible Urticaria (CIndU) Pressure Cholinergic Cold Heat Friction UV light

9 Classification of chronic urticarias Spontaneous Urticaria Due to known cause Due to unknown cause No specific trigger Inducible Urticaria Symptomatic Dermographism Cold Contact Urticaria Solar Urticaria Delayed Pressure Urticaria Heat Contact Urticaria Vibratory Urticaria Specific trigger Contact Urticaria Aquagenic Urticaria Cholinergic Urticaria Zuberbier et al., Allergy 2014: 69;

10 Prevalence of chronic spontaneous urticaria Prevalence: 0.5 1% may be increasing Maurer et al., Allergy 2011: 66;

11 Prevalence of chronic spontaneous urticaria Prevalence: 0.5 1% may be increasing Europe: World: 8 Million patients 80 Million patients Maurer et al., Allergy 2011: 66;

12 Chronic spontaneous urticaria is chronic > 6 weeks: 100% > 6 months: 50% > 10 years: 20% Maurer et al., Allergy 2011: 66;

13 Chronic spontaneous urticaria is chronic > 6 weeks: 100% > 6 months: 50% > 10 years: 20% 5-7 years on average Maurer et al., Allergy 2011: 66;

14 Chronic urticaria is a common, disabling, and complex disease.

15 Urticaria Pathogenesis Mast cells are the key effector cells in the induction of urticaria symptoms. C A U S E IgE SCF IgG LPS Complement Anaphylatoxins Neuropeptides Endothelin-1 Bacteria Interleukins Chemokines Oxytocine Leukotriene POMCs Prostaglandins Cannabinoids Adenosine Urokinase Capsaicin? Fc e RI Kit Fc g 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-g, 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 Urticaria and Angioedema. Zuberbier T, Grattan C, Maurer M (eds.).springer 2010

16 Wheal and flare Angioedema

17 Urticaria Wheal and flare Angioedema

18 Urticaria Wheal and flare Angioedema

19 Urticaria Wheal and flare Angioedema

20 50% 40% 10% Wheal and flare Angioedema

21 Urticaria - Therapeutic strategies Trigger Cause Mast cellactivating signal Mast cell activation Mast cell mediators Urticaria reaction causal symptomatic Urticaria and Angioedema. Zuberbier T, Grattan C, Maurer M (eds.).springer 2010

22 Urticaria - Therapeutic strategies Trigger Cause Mast cellactivating signal Mast cell activation Mast cell mediators Wheals Angioedema causal symptomatic Urticaria and Angioedema. Zuberbier T, Grattan C, Maurer M (eds.).springer 2010

23 Urticaria - Therapeutic strategies Trigger Cause Mast cellactivating signal Mast cell activation Mast cell mediators Wheals Angioedema causal symptomatic Urticaria and Angioedema. Zuberbier T, Grattan C, Maurer M (eds.).springer 2010

24 Urticaria - Therapeutic strategies Trigger Cause Mast cellactivating signal Mast cell activation Mast cell mediators Wheals Angioedema causal symptomatic Urticaria and Angioedema. Zuberbier T, Grattan C, Maurer M (eds.).springer 2010

25 Urticaria - Therapeutic strategies Trigger Cause Mast cellactivating signal Mast cell activation Mast cell mediators Wheals Angioedema causal symptomatic Urticaria and Angioedema. Zuberbier T, Grattan C, Maurer M (eds.).springer 2010

26 What is the goal of treating patients with chronic urticaria? Absence of symptoms Treat the disease until it is gone

27 Urticaria Control Test (UCT) Is your urticaria under control? Weller et al., J. Allergy Clin. Immunol. 2014: 133;

28 Urticaria Control Test (UCT) Weller et al., J. Allergy Clin. Immunol. 2014: 133;

29 Urticaria Control Test (UCT) 0 points 1 point 2 points 3 points 4 points 0 points 1 point 2 points 3 points 4 points 0 points 1 point 2 points 3 points 4 points 0 points 1 point 2 points 3 points 4 points Weller et al., J. Allergy Clin. Immunol. 2014: 133;

30 Urticaria Control Test (UCT) 12 = Weller et al., J. Allergy Clin. Immunol. 2014: 133;

31 Urticaria Control Test (UCT)

32 Urticaria Control Test Denmark Norway UK Sweden Poland The Netherlands Hungary Canada Bulgaria (French) France Serbia Korea Canada Azerbaijan (Engl.) Spain China USA Turkey Portugal Dubai Mexico Israel Thailand Italy Greece India Egypt Russia Brazil Lebanon Australia translation completed translation not started translation in progress

33 Treatmetn of chronic urticaria How do we help our patients to get their urticaria under control?

34 EAACI / GA 2 LEN / EDF / WAO Urticaria Guidelines: 2013 Revision and Update Second-generation H 1 -Antihistamine (sgah) If symptoms persist after 2 weeks Increase sgah dose (up to 4x) If symptoms persist after 1-4 weeks Add Omalizumab, Cyclosporine A, or Leukotrieneantagonist Short course systemic corticosteroid may be tried for exacerbations Zuberbier et al., Allergy 2014: 69;

35 EAACI / GA 2 LEN / EDF / WAO Urticaria Guidelines: 2013 Revision and Update Second-generation H 1 -Antihistamine (sgah) Zuberbier et al., Allergy 2014: 69;

36 EAACI / GA 2 LEN / EDF / WAO Urticaria Guidelines: 2013 Revision and Update Second-generation H 1 -Antihistamine (sgah) If symptoms persist after 2 weeks Increase sgah dose (up to 4x) 2013 Urticaria Guideline Revision and Update

37 Asleep Awake Effects of sedating antihistamines First Generation Antihistamine Awake Drowsy REM Sleep delayed and reduced REM Sleep Night Day Night Day Church, Maurer,..., Zuberbier. Allergy 2010; 65:

38 Pruritus reduction (in %) Combination vs. Updosing 100 *** ** 80 AH AH 1 AH 2 AH AH 1 AH x 2 3 x 2 4 x 1 Combination Updosing Schulz et al., Hautarzt 2009

39 EAACI / GA 2 LEN / EDF / WAO Urticaria Guidelines: 2013 Revision and Update Second-generation H 1 -Antihistamine (sgah) If symptoms persist after 2 weeks Increase sgah dose (up to 4x) 2013 Urticaria Guideline Revision and Update

40 Patients (in %) Patients sufficiently treated with antihistamines 45% 65% ns-ah (regular dose) ns-ah (high dose)

41 Increasing the dose of anithistamines Weller et al., PLoS ONE 2011

42 Non sedating, modern, second generation antihistamines are the first line treatment! Which one should I use? How do I choose?

43 Updosed AHs work better! EXAMPLE: Cold urticaria

44 Cold Urticaria

45

46 Trigger Threshold Assessment in Cold Urticaria

47 Trigger Threshold Assessment in Cold Urticaria

48

49

50 44 C 24 C 4 C 22 C

51 Updosing of Bilastine improves protection from cold in patients with cold urticaria! Krause et al., Allergy 2013: 68;

52 Updosing of Bilastine improves protection from cold in patients with cold urticaria! Krause et al., Allergy 2013: 68;

53 Updosing of Bilastine improves protection from cold in patients with cold urticaria! Krause et al., Allergy 2013: 68;

54 Updosing of Bilastine improves protection from cold in patients with cold urticaria! Krause et al., Allergy 2013: 68;

55 Updosing of Bilastine in cold urticaria patients increases the number of complete responders! Complete response* n Partial response** Placebo 1 (5%) 2 (10%) n BL 20 mg 7 (35%) 8 (40%) BL 40 mg 11 (55%) 6 (30%) BL 80 mg 12 (60%) 7 (35%) *No wheal-and flare reaction at lowest temperature (4 C) **Reduction in temperature threshold >5 C Krause et al., Allergy 2013: 68;

56 Updosed AHs work better! EXAMPLE: Chronic spontaneous urticaria

57 Updosing of Bilastine in CSU No therapy* *Rescue medication (bilastine 20mg) if no CR Bilastine 20mg Bilastine 40mg Week if no CR Bilastine 80mg Daily documentation of the UAS (wheal number / pruritus intensity) CU-Q 2 ol completion Weller et al., Unpublished data

58 Updosing of Bilastine improves chronic spontaneous urticaria! UAS7 Values Baseline 20 mg 40 mg 80 mg Bilastine Weller et al., Unpublished data

59 Updosing of Bilastine improves chronic spontaneous urticaria! Patients with minimal urticaria activity and minimal pruritus (in %) UAS7 6 Pruritus7 3 Weller et al., Unpublished data

60 EAACI / GA 2 LEN / EDF / WAO Urticaria Guidelines: 2013 Revision and Update Second-generation H 1 -Antihistamine (sgah) If symptoms persist after 2 weeks Increase sgah dose (up to 4x) If symptoms persist after 1-4 weeks Add Omalizumab, Cyclosporine A, or Leukotrieneantagonist Short course systemic corticosteroid may be tried for exacerbations 2013 Urticaria Guideline Revision and Update

61 Wheal Score 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;

62 Change in UAS7 Omalizumab works in CSU Omalizumab Placebo 75 mg 150 mg 300 mg *** *** Maurer et al., N. Engl. J. Med. 2013: 368;

63 Responders (in %) UAS7 6 at Week 12 Omalizumab works in CSU *** *** Placebo 75 mg 150 mg 300 mg Omalizumab Maurer et al., N. Engl. J. Med. 2013, in press

64 Omalizumab works in CSU Omalizumab 300 mg *** Omalizumab 150 mg *** Omalizumab 75 mg Placebo Improvement in QoL (DLQI score) Maurer et al., N. Engl. J. Med. 2013: 368;

65

66 EAACI / GA 2 LEN / EDF / WAO Urticaria Guidelines: 2013 Revision and Update Second-generation H 1 -Antihistamine (sgah) If symptoms persist after 2 weeks Increase sgah dose (up to 4x) If symptoms persist after 1-4 weeks Add Omalizumab, Cyclosporine A, or Leukotrieneantagonist Short course systemic corticosteroid may be tried for exacerbations 2013 Urticaria Guideline Revision and Update

67 GA 2 LEN Global Urticaria Forum URTICARIA 2016: Guideline Consensus Conference globalurticariaforum.org; urticariaguideline.org

68 Division of Dermatological Allergology

69 Backup Slides

70 Bilastine reduces proinflammatory cytokine levels in vivo! Interleukin 6 Interleukin 8 Krause et al., Allergy 2013: 68;