Mast Cell Mediators. Updates on Chronic Urticaria 11/1/2016. Urticaria: What happens in the skin?

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1 Urticaria: What happens in the skin? Updates on Chronic Urticaria Kent Woo, MD (USA) Allergy/Immunology Internal Medicine C A U S E MC, mast cell IgE Fc eri MC Release of Mediators Activation Vasodilation Extravasation Recruitment PRURITUS ERYTHEMA WHEAL INFILTRATE Mast cells are the key effector cells in the induction of urticaria symptoms Urticaria and Angioedema. Zuberbier T, Grattan C, Maurer M, editors. Berlin: Springer-Verlag, 2010 Mast Cell Mediators Mediators causing wheal and flare - Histamine - Bradykinin - PGE 2/PGD 2 - LTC 4 /LTD 4 /LTE 4 - PAF Mediators causing prolonged erythema - PGE 2 / PGD 2 /PGI 2 Mediators enhancing urticarial reactions - Proteases: increase vascular permeability - Chemotactic factors - Cytokines Objective: To evaluate the initiators of blood coagulation that lead to thrombin generation and fibrinolysis in CU. Methods: 37 patients with CU and 37 controls Activated factor VII, activated factor XII, fragment F1+2, and D-dimer plasma levels were measured Skin specimens from 10 patients with CU and 10 controls were tested for tissue factor immunohistochemically 3, >20 immunoreactive cells 2, 6-20 immunoreactive cells 1, 1-5 immunoreactive cells 0, No immunoreactive cells Plasma prothrombin fragment F1+2 levels in patients and controls Scores of tissue factor immunoreactivity in tissue samples 1

2 Plasma D-dimer levels as measured by ELISA Plasma FVIIa levels in patients and controls Conclusion: The extrinsic pathway of clotting cascade is activated in CU Disease severity is associated with the activation of the coagulation cascade The involvement of the coagulation pathway in CU opens new perspectives of the pathogenesis and, for the treatment of this disease. Ninety-one patients with Chronic Urticaria Male/Female: 22/69 Mean age: 46.9 years, median: 47 years (Range, 11-85) Mean disease duration was 28.6 months (median 5 months) x-axis: 1, excellent; 2, good; 3, partial; 4, poor; 5, no response to the drug This study suggests that elevated D-dimer levels can be considered as a biomarker for antihistamine-resistant CU A supplementary mechanism of inflammation is suggested in patients with CU showing an activation of fibrinolysis Individual levels of D-dimer in patients showing CU of different severity 2

3 Objective: This study aimed to find the relationship between plasma D-dimer levels and the disease severity of Thai CU patients Methods: - We retrospectively reviewed case record forms of chronic idiopathic urticaria (CIU) patients patients, 30 male (25%) and 90 female (75%) - Mean age of 38.8 years (range years) - Recruited from Skin Allergy Clinic, Siriraj Hospital Mahidol University, Bangkok, during June 2008 to June Plasma D-dimer levels of chronic idiopathic urticaria patients with mild, moderate and severe disease activity Asero J Allergy Clin Immunol May;135(5): Conclusion: This study showed elevated plasma D-dimer levels in nearly half of Thai patients with CIU There was a positive correlation between plasma D-dimer levels and the severity of disease activity Asero J Allergy Clin Immunol May;135(5): History of the main studies of coagulation in chronic spontaneous urticaria These observations confirm that D-dimer is a good marker of disease activity in most patients with spontaneous CU, and show that such parameter may also be useful to monitor the clinical response to ciclosporin treatment in most patients with severe disease. 3

4 Extrinsic pathway of the coagulation cascade is activated in chronic urticaria via Eosinophil Tissue Factor Extrinsic activation appears to lead to thrombin generation Immune mechanisms in Urticaria Tissue Factor Trigger Mast Cell Degranulation WAO Journal 2009 WAO Journal 2009 Vitamin D has many functions Methods: The clinical records of 72 patients with chronic urticaria, 26 with acute urticaria and 26 with atopic dermatitis, along with 72 healthy controls, were retrospectively reviewed. Vit D3 levels were significantly reduced in patients with chronic urticaria The proportion of subjects with critically low vitamin D was significantly higher in patients with chronic urticaria 4

5 Vit D 3 levels had inverse relationship with the UAS 192 subjects with CU stratified according to the baseline Vit D levels Randomized into three subgroups to receive for 6 weeks: - Vit-D 3 alone - Antihistamine and systemic corticosteroid - Vit-D 3 with antihistamine and systemic corticosteroid 130 healthy controls (HC) were followed The patients were evaluated using visual analogue scale (VAS) and 5-D itch score **P < 0.01 ***P < Effect of Vitamin D supplementation in different therapy protocols for CU * P < 0.05 ** P < 0.01 *** P < Vit D status in CU patients and healthy controls at baseline and after 6 weeks of treatment Treatment Conclusions: CU patients have low serum 25(OH) 2 D levels Vit-D 3 supplementation in combination with antihistamine and systemic corticosteroid show elevated response in resolving the symptoms of CU 5

6 Objective: The expected timing of response to omalizumab has not been previously reported. Furthermore, published data do not provide guidance on how many doses might be needed to define response or lack of response. Methods: Every 4 weeks, randomized patients received dosing with placebo or 75, 150, or 300 mg of omalizumab (ASTERIA I: N=318, 24 weeks; ASTERIA II: n=322, 12 weeks) or placebo or 300 mg of omalizumab (GLACIAL: n=335, 24 weeks) Response was defined as well-controlled urticaria (weekly Urticaria Activity Score [UAS7] 6) or complete response (UAS7 = 0). Response patterns to treatment of CIU/CSU with omalizumab were dose dependent Use of the 300-mg dose of omalizumab resulted in the largest percentage of patients who achieved a complete response (UAS7 = 0) or well-controlled urticaria (UAS7 6) Percentage of nonresponders at week 12 who responded by week 24 Half of the patients treated with 300 mg of omalizumab had well-controlled symptoms after 2 injections (median time to response, 6 weeks). The benefits of omalizumab treatment in patients with CIU/CSU were evident to week 24 6

7 ... 11/1/2016 The timing of well-controlled and complete response suggests that there might be 2 categories of responders to omalizumab: - Those who respond early (before week 4) - Those who require more than 3 monthly doses to respond Rapid itch reduction after the 1st dose with Omalizumab 300 mg 2 Rapid reduction** Mean change from baseline in weekly ISS by study week (baseline observation carried forward method, modified intention-to-treat population)....discontinuation of Omalizumab Itch re-emerges after end of treatment * adapted from Kaplan A, et al * Mean weekly ISS increased to values similar to those in the placebo group after Week 12, but did not return to baseline values. Itch relief was defined by a reduction in weekly ISS by 5 points from baseline 6 ** Time to achieve minimally important difference in weekly itch severity score was 2 weeks with Omalizumab. 2 Patients were receiving background treatment of non-sedating H1-antihistamines (up to 4x the approved dose) plus H2-antihistamines and/or leukotriene-receptor antagonists. Data represent the modified intention-to-treat (mitt) population; ISS, itch severity score. P <.001 for the comparison with placebo at week 12 Just be on Urticaria Day 1 st October