2012/12/5. Principle of the management of urticaria. The efficacy of systemic steroid on urticaria depends of subtypes urticaria

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1 6 December 2012: 13:3015:00 G.04 (HICC) The Hyderabad International Convention Centre (HICC) in Hyderabad, India WISC 2012; WAO International Scientific Conference Postgraduate Course 16: URTICARIA & ANGIOEDEMA TRACK Understanding and Managing Acute and Chronic Urticaria Approach to Refractory Urticaria and Chairpersons: Korad Bork (Germany), Sarbjit Saini (United States) Michihiro Hide, MD, Ph.D Department of Dermatology, Graduate School of Biomedical Sciences Hiroshima University Frequently raised complaints by patients with and angioedema 1.Intolerable symptoms in spite of treatments Health is a state of complete physical, mental and social wellbeing and not merely the absence of disease or infirmity. (Definition of health in the WHO constitution) Frequently raised complains by patients with and angioedema 1.Intolerable symptoms in spite of treatments Health status scores in patients with CSU are comparable to those in patients with coronary artery disease 2.What is the cause of my? Food?, Sick of internal organs?, etc. 3.How long does it take for cure? Please treat at causative level, not symptomatically Do I suffer from for life long? 4.I don t like drugs just for symptoms I don t want to be dependent on drugs. Principle of the management of In general, Urticaria inducible by certain stimuli are resistant for medications. whereas Urticaria characterized by spontaneously appearing wheals are subject to medications, especially antihistamines. Chronic spontaneous Mechanical Without treatment The efficacy of systemic steroid on depends of subtypes Under treatment Subtypes of Spontaneous Inducible type s Expectable Acute and chronic spontaneous (including autoimmune ) Delayed pressure (DPU) Spontaneous/idiopathic (histaminergic) t expectable Urticarias due to type I allergy and NSAIDs intolerance, the other physical s, etc. Other types of angioedema, HAE ACEI induced angioedema, etc. Symptoms of CSU may be completely suppressed, but those of mechanical are partially suppressed only. Diseases related to Urticarial vasculitis Urticaria pigmentosa, Schnitzler syndrome, CAPS 1

2 Principle of the management of It is important to distinct acute and chronic spontaneous (CSU) from the other types of, not only because the absence of direct trigger for exciting wheal formation, but also because responsiveness to treatments, especially steroids. Principle of the management of 自発的に皮疹が Inducible 現れる Diagnosis: subtype spontaneous Make clear the aim and options of treatments Drug therapies for symptoms(antihistamines) Remove or avoid causes/aggravating factors Adopted from Guidelines for Management of Urticaria. Jap J Dermatol 121: , 2011 (in Japanese), & Allergol Int 2012 [Epub ahead of print] suggested by guidelines: BSACI, 2007 Management of chronic spontaneous (CSU) IDENTIFICATION OF TRIGGERS EDUCATION AND AVOIDANCE OF TRIGGERS 6) Add or substitute other second line agents, such as a ciclosporin or low dose corticosteroid 5) Consider adding or substituting with second line agent, e.g. antileukotriene (or tranexamic acid if angiooedema is present) 4) Consider sedating antihistamine at night 3) Add second non sedating H1antihistamine (regular or required) 2) Higher dose of H1antihistamine 1) Standard dose non sedating H1antihistamine Powell RJ, et al. BSACI guidelines for the management of chronic and angiooedema. Clin Exp Allergy 2007; 37: suggested by guidelines: EAACI, 2009 n sedating H1 antihiatamine (nsah) after 2 weeks nsah updosing (up to 4 ) After 1 4 weeks Add Leukotriene antagonist or change nsah Exacerbation: Systemic Steroid (for 37 days) After 1 4 weeks Add Ciclosporin A, H2 antihistamine, Dapsone, Omalizumab Exacerbation: Systemic Steroid (for 37 days) Zuberbier T, et al. EAACI/GA(2)LEN/EDF/WAO guideline: management of. Allergy 2009; 64: suggested by guidelines: JDS, Antihistamines 2Supplementary medications 4Experimental trials 1standard doses, 2change drugs, 3increase doses e.g. H2blockers*, antileukotrienes*, extracts of inflammatory rabbit skin inoculated with vaccinia virus, glycyrrhizinic acid, dapsone, antianxiety drugs, tranexamic acid *Off label use corticosteroids, equivalent to 515 mg/day prednisolone immunological treatments (e.g. CisA*, corticosteroids, equivalent >20 mg/day) Hide M, et al. Guidelines for Management of Urticaria. Jap J Dermatol 121: , 2011 (in Japanese), & Allergol Int 2012 [DOI: /allergolint.12RAI0497] 2

3 Stages of the refractory and angioedema 1. Intolerable symptoms in spite of vigorous treatments 2. or mild symptoms on heavy load of treatments (adverse effects, cost, cumbersomeness) 3. or mild symptoms on treatments with mild or moderately heavy load of treatments 4. or mild symptoms on safe and readily available treatments, such as antihistamines, but recur if stop medication Algorism for treatment of chronic idiopathic (spontaneous) Diagnose and confirm objectives in treatment Oral antihistamines (1~2 wks) Symptoms disappeared or improved Continue the same treatment for1~2 months* Fig.3 Change to other drugs, or consider to increase the level of treatment (Fig. 3) *take into account the time to symptoms free, kinds and amounts of oral medications, etc.. 1 Antihistamines 2 Supplementary medications 4 Experimental trials Continue present treatment Benefits overcome disadvantages, such as adverse effects, costs Step up to Tx in Fig.3 Evaluation of disease severity and the necessity of further medication Guidelines for Management of Urticaria. Jap J Dermatol 121: , 2011 (In Japanese), Allergol Int Oct 25. [Epub ahead of print] Three points to be taken for the management of refractory and angioedema 1. How to suppress apparent symptoms? 2. How to control underlying disease activities towards remission/cure? 3. Balance for the effect and burdens 4. Time course towards the remission/cure Treatments for CSU that is not sufficiently controlled by level 1 treatment (nsah, 1x): EAACI guideline, 2009 Level Medication Cost Safety profile Evidence for efficacy 2nd nsah updosing (up to 4x) Low Good Good 3rd 4th add LT antagonist or change nsah Lowto mediumlow Good Insufficient or no evidence in high quality RCT CisA Medium to high Moderate Very low level H2antihistamine Low Good Very low level Dapsone Low Medium level of side effects Low level Omalizumab High Good High level Saini S, et al. J Allergy Clin Immunol 2011; 128: Increasing number of reports about the efficacy of omalizumab has been published. It is beyond both serum IgE concentrations and subtypes Immunosuppuressive/modulative treatments for Steroid(PDN>20mg/d) Plasmapheresis CisA Methotrexate Cyclophosphamide IVIG Mycophenolate Hydroxychloroquine Omalizumab * For autoimmune Chronic ** * ** * * * * ** (RCT) Other type Anaphylaxis solar ** (RCT) cholinergic, cold, etc * For non autoimmune *The effectiveness is for reducing/suppressing symptoms, not necessarily for cure. They may also applied for nonautoimmune 3

4 Algorism for treatment of chronic idiopathic (spontaneous) Diagnose and confirm objectives in treatment Oral antihistamines (1~2 wks) Symptoms disappeared or improved Continue the same treatment for1~2 months* Fig.3 Change to other drugs, or consider to increase the level of treatment (Fig. 3) *take into account the time to symptoms free, kinds and natures of medications, etc.. 1 Antihistamines 2 Supplementary medications 4 Experimental trials Continue present treatment Benefits overcome disadvantages, such as adverse effects, costs Step up to Tx in Fig.3 Adapted from Guidelines for Management of Urticaria. Jap J Dermatol 121: , 2011 (In Japanese), Allergol Int Oct 25. [Epub ahead of print] CQ12:Should idiopathic continued to be treated for a certain period after a disappearance of symptoms? Comments:Idiopathic should continued to be treated for a while after disappearance or decrease of the symptoms. Recommendation level:b, Evidence level II References: 1) Grob JJ, et al: How to prescribe antihistamines for chronic idiopathic : desloratadine daily vs PRN and quality of life, Allergy, 2009; 64: ) Furukawa F, et al:the comparison of proactive and reactive treatments on chronic. (in Japanese), Rinshou Hifuka, 2009; 63: ) Kawashima M, Kohno T:The effect of different durations of proactive treatment with antihistamine on the prognosis of chronic. (in Japanese), Rinshou Hifuka, 2010; 64: Guidelines for Management of Urticaria. Jap J Dermatol 121: , 2011 (In Japanese), Allergol Int Oct 25. [Epub ahead of print] Management of inducible type Inducible type s are mostly refractory to antihistamines Physical Mechanical (Symptomatic Dermographism) Cold Solar ** Heat Delayed pressure (DPU) Other types Cholinergic ** Aquagenic *Avoidance of exciting factor Contact * **Hardening/tolerance induction Allergic * (except for bradykinin mediated angioedema) Reported treatments for inducible type s Mechanical Cold Solar Heat Aquagenic DPU Cholinergic Contact Allergic Avoid Hardening triggers /tolerance ~ Steroids Omalizu mab Mechanical (especially with severe itching) 4

5 Effects of Ciclosporin on refractory mechanical Age Duration CsA dose Duration of CsA, /Sex (yr) (mg/kg/ day) (month) Previous medications Outcome Adverse effects 1 56/M H 1 antagonists in 3fold doses, corticosteroids ( 5mg/day, 2 Cure ne H 1 antagonists in 3fold doses, leukotriene antagonists, Improvem 2 67/F , continue corticosteroids (2.520mg/day, 2 ent ne years) 3 25/F , continue H 1 antagonists in 3fold doses, H 2 antagonists, leukotriene Improvem Epigastric antagonists, ent distress corticosteroids (2.57.5mg/day, 2 years) H 1 antagonists in 3fold doses, leukotriene antagonists, Improvem 4 26/F , continue corticosteroids (1030mg/day, 2 ent ne 5 65/F /M H 1 antagonists in 4fold doses, corticosteroids (5mg/day, 2 H 1 antagonists in 3fold doses, leukotriene antagonists Inefficien cy ne Inefficien Headache, cy nausea Toda S, et al. Allergol Int 2011; 60: Taxonomy of the treatment for and view points for practice Short time, temporary actions Adrenalin injection Antihistamine (iv, im, po), Steroid infusion Plasmapheresis, IVIG, etc Long time control Antihistamine Auxiliary medications Oral steroids, etc Long time remission, cure Desensitization Prophylactic use of antihistamines, etc HAE Allergic Chronic spontaneous Taxonomy of the treatment for and view points for practice Short time, temporary actions Adrenalin injection Antihistamine (iv, im, po), Steroid infusion Plasmapheresis, IVIG, etc Long time control Antihistamine Auxiliary medications Oral steroids, etc Long time remission, cure Desensitization Prophylactic use of antihistamines, etc Effects on symptoms Effects on symptoms Burden for patients (safety, cost, convenience, etc.) Effects on disease itself Principle of the management of Diagnosis of disease subtype Inducible 自発的に皮疹が現 れる Spontaneous Make clear the aim and options of treatments Drug therapies for symptoms (antihistamines, etc) Remove or avoid Causes/aggravating factors symptoms under treatments (Remittance of disease activities) symptoms without treatments Thank you for your listening Night scene in Hiroshima 5