chronic urticaria

diagnosis and treatment of chronic urticaria

1. Updates in Chronic Urticaria Management BY PROF. ASHRAF OKBA HEAD OF THE DEPARTMENT OF IMMUNOLOGY AND ALLERGY AIN SHAMS UNIVERSITY

2. Agenda 2 Introduction and definitions Prevalence Mast cell and urticaria pathogenesis Diagnosis Urticaria burden Assessment of disease severity and patient quality of life Guidelines updates in u rticaria treatment

3. 3 Urticaria is a common disease with many different clinical presentations. Dermatologists, allergists, accident and emergency specialists, general physicians, paediatricians and general practitioners may see a quite different selection of cases, and this may cause confusion. 1-5 Introduction 1 Champion RH, Greaves MW, Kobza Black A, Pye RJ, eds. The Urticarias . Edinburgh : Churchill Livingstone, 1985. 2 Schocket AL, ed. Clinical Management of Urticaria and Anaphylaxis . New York: Dekker , 1993. 3 Henz BM, Zuberbier T, Grabbe J, Monroe E, eds. Urticaria: Clinical, Diagnostic and Therapeutic Aspects . Berlin: Springer, 1998. 4 Dreskin SC, ed. Urticaria [special issue]. Immunol Allergy Clin N Am 2004; 24 (2). 5 Greaves MW, Kaplan AP, eds. Urticaria and Angioedema. New York: Decker, 2004 .

4. Urticaria is a disease characterized by the development of wheals (hives), angioedema, or both. Urticaria Definition : Acute urticaria is defined as the occurrence of spontaneous wheals , angioedema, or both for <6 weeks , while in chronic urticaria symptoms last for more than 6 weeks. Zuberbier T, Aberer W, Asero R, et al. The EAACI/GA²LEN/EDF/WAO guideline for the definition, classification, diagnosis and management of urticaria. The 2013 revision and update. Allergy 2014;69:868–87

5. Clinical Appearance Wheals have three typical features: Central swelling of variable size, almost invariably surrounded by a reflex erythema Associated with itching or sometimes a burning sensation Fleeting nature, with the skin returning to its normal appearance , usually within 1–24 hours. Sometimes wheals resolve even more quickly Zuberbier T, Aberer W, Asero R, et al. The EAACI/GA²LEN/EDF/WAO guideline for the definition, classification, diagnosis and management of urticaria. The 2013 revision and update. Allergy 2014;69:868–87

6. Angioedema Definition / an·gio·ede·ma /  a vascular reaction involving the deep  dermis  or subcutaneous or  submucosal   tissues,representing  localized  edema  caused by dilatation and increased permeability of the capillaries, Sometimes pain rather than itching. Frequent involvement below mucous membranes Its resolution is slower than that for wheals and can take up to 72 hours 1 Angioedema most often involves the eyelids , lips, tongue, genitalia, hands and feet with the larynx , gastrointestinal and urinary bladder being less commonly affected. Zuberbier T, Aberer W, Asero R, et al. The EAACI/GA²LEN/EDF/WAO guideline for the definition, classification, diagnosis and management of urticaria. The 2013 revision and update. Allergy 2014;69:868–87 Angio-oedema of the lip (a) during and (b) 3 days after an attack . ( Courtesy of St John’s Institute of Dermatology, London, UK.)

7. 7 Acute Urticaria: ˂ 6 Weeks Chronic Urticaria: ≥ 6 Weeks Classification of Urticarias Zuberbier T, Aberer W, Asero R, et al. The EAACI/GA²LEN/EDF/WAO guideline for the definition, classification, diagnosis and management of urticaria. The 2013 revision and update. Allergy 2014;69:868–87

8. Classification of Urticarias 1 1. Adapted from: Zuberbier T, et al. Allergy 2014;69 (7):868–87. Chronic spontaneous urticaria Chronic Acute Spontaneous Inducible Urticaria Known causes (including autoimmunity, infection, food components, etc ) Unknown causes Chronic spontaneous urticaria (CSU) can be defined as the spontaneous daily, or almost daily, occurrence of itchy hives, angioedema or both, due to known or unknown causes, and lasting for 6 weeks or more Symptoms daily or almost daily for ≥6 weeks No obvious external specific trigger Symptoms for <6 weeks Symptoms induced by a specific trigger, e.g. temperature, pressure, cholinergic 10 New 2013

9. Chronic Urticaria: What is in Name? Is it chronic urticaria, chronic idiopathic urticaria, or chronic spontaneous urticaria ? The term chronic indicates that urticaria is present for more than 6 weeks. The cause of chronic urticaria is known in approximately 25% of patients (refers primarily to those with physically inducible urticarias ) Kaplan AP. Therapy of chronic urticaria: a simple, modern approach. Ann Allergy Asthma Immunol.2014 (Article in press)

10. For CSU, the cause of the spontaneous urticarias approaches zero because the etiology is not known even though there is an association with autoimmunity in approximately 45% of patients and , T he term spontaneous rather than idiopathic emphasizes that it is endogenous rather than exogenous and non inducible rather than inducible. Chronic Urticaria: What is in Name? Kaplan AP. Therapy of chronic urticaria: a simple, modern approach. Ann Allergy Asthma Immunol.2014 (Article in press)

11. Chronic urticaria Now classified into spontaneous and inducible forms 2013 guidelines* classify chronic urticaria into “ spontaneous ” and “ inducible ” 2 Chronic Urticaria Subtypes Chronic spontaneous urticaria Inducible urticaria Spontaneous appearance of wheals, angioedema or both ≥6 weeks due to known 1 or unknown causes The term “ Chronic Idiopathic Urticaria” should be avoided Physical urticarias Symptomatic dermographism 2 Cold urticaria 3 Delayed pressure urticaria 4 Solar urticaria Heat urticaria 5 Vibratory angioedema Cholinergic urticaria Contact urticaria Aquagenic urticaria 1. For example, autoreactivity, i.e. the presence of mast cell-activating autoantibodies ; 2. also called urticaria factitia , dermographic urticaria; 3. also called cold contact urticaria; 4. also called pressure urticaria; 5. also called heat contact urticaria Revised in the 2013 guidelines *Guidelines: EAACI, European Academy of Allergology and Clinical Immunology GA 2 LEN, Global Allergy and Asthma European Network EDF, European Dermatology Forum WAO, World Allergy Organization Zuberbier T, et al. Allergy 2009;64:1417–26 ; Zuberbier T, Aberer W, Asero R, et al. The EAACI/GA²LEN/EDF/WAO guideline for the definition, classification, diagnosis and management of urticaria. The 2013 revision and update. Allergy 2014;69:868–87

12. Prevalence of Urticaria Estimated to occur in 15-23% of the population Up to 40% of patients who have chronic urticaria longer than six months will still have urticaria 10 years later Approximately 40% of patients with chronic urticaria have angioedema All age groups can be affected, however the peak incidence is seen between 20 and 40 years of age. i.e , patients are primarily affected during important years of their working age.

13. Prevalence of Urticaria With and Without Angioedema

14. Urticaria Acute urticaria refers to hives lasting less than six weeks; in approximately 15-20% of cases an inciting cause can be identified Chronic urticaria refers to hives lasting longer than 6-8 weeks; identification of a cause is less than 5%

15. Chronic spontaneous Urticaria is by far the most common subtype of all forms of non-acute Urticaria. 1 The duration of CSU varies greatly from patient to patient , with some individuals suffering irritating symptoms such as pruritus far decades. 2 2- A/ fergol et lmmunopatho /2001; 29(4): 129-132 1- Allergy 2011; 66: 317–330. Prevalence and Burden

16. Frequency of angioedema in selected patients with chronic spontaneous urticaria n, number of patients/subjects; NR, not reported. *Authors examined patients with all types of urticaria. † Authors do not distinguish between chronic spontaneous urticaria and other forms of nonacute urticaria. ‡ Authors examined the total population. Maurer M, Weller K, Bindslev -Jensen C, Giménez-Arnau A, Bousquet PJ, et al. Unmet clinical needs in chronic spontaneous urticaria. A GA²LEN task force report. Allergy. 2011 Mar;66(3):317-30

17. In most cases, the duration of CSU is estimated to be 1–5 years 1 However, for some patients the disease can last longer, sometimes more than 25 years 1 Year 25 Years since diagnosis Another 20% will resolve (with or without treatment) within 5 years of onset 2 50% will resolve (with or without treatment) within 6 months of onset 2 Another 20% will resolve ( with or without treatment) within 3 years of onset 2 Another <2% will resolve (with or without treatment) within 25 years 2 Duration of Chronic Urticaria Year 1 Year 2 Year 3 Year 4 Year 5 1. Maurer M, et al. Allergy 2011;66:317–30; 2 . Beltrani VS. Clin Rev Allergy Immunol 2002;23:147 – 69

18. 18 CINDU: Chronic inducible Urticaria Maurer M1, Weller K, Bindslev -Jensen C, Giménez-Arnau A, Bousquet PJ, et al. Unmet clinical needs in chronic spontaneous urticaria. A GA²LEN task force report. Allergy. 2011 Mar;66(3):317-30

19. 19 MC Release of Mediators including H istamine PRURITUS ERYTHEMA WHEAL INFILTRATE Activation Vasodilation Extravasation Recruitment C A U S E 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 MC, mast cell Urticaria Pathogenesis S ymptoms are brought about by the degranulation of skin mast cells I gE Fc e RI

20. Altrichter S, et al. PLoS One 2011;6:e14794; Hide M, et al. N Engl J Med 1993;328:1599−604 Mast cells in some patients are activated by autoallergic or autoimmune mechanisms 1 his tamine -releasing immunoglobulin G (IgG) autoantibodies against the high-affinity immunoglogulin E (IgE) receptor ( Fc ε RI ) or IgE itself are present in the circulation, 2 and IgE autoantibodies may also be present 1 Auto-allerg y allergen 1.Autoantigen/autoallergen 3. endogenous anti-IgE antibody Auto-immunit y 2. anti-Fc ε RI 1.IgE against self Allerg y MC IgE Fc ε RI Pathophysiology of urticaria Mast cell stimulation

21. Several mechanisms of mast cell activation in CU have been identified : For example, IgG autoantibodies directed against IgE can cause cross-linking of mast cell– bound IgE and subsequent mast cell degranulation. Another subgroup of patients with CU exhibits IgG autoantibodies directed against the a-subunit of the high-affinity IgE receptor FceRI on mast cells . R ecently identified, a subgroup of patients with CU who exhibit IgE autoantibodies against thyroperoxidase (TPO), and IgE antibodies against TPO ( IgE– anti-TPO )–positive patients with CU exhibit significantly higher IgG–anti-TPO levels and lymphocyte counts, as well as decreased C4 complement levels CU: Chronic urticaria (J Allergy Clin Immunol 2011;128:202-9.) Pathophysiology of urticaria (Cont.) Mast cell stimulation

22. 22 Complement Ca5 Thrombin Fc ἐ RI IgG autoantibodies Auto-antigen:TPO IgE autoantibodies mRNA Free IgE Pathophysiology of urticaria (Cont.) Mast cell stimulation The slide is for illustrative purpose

23. 23 Complement Ca5 Thrombin Fc ἐ RI Free IgE IgG autoantibodies Auto-antigen:TPO IgE autoantibodies mRNA Pathophysiology of urticaria (Cont.) Mast cell stimulation ( Immune-mediated urticaria ) The slide is for illustrative purpose

24. Maurer M1, Weller K, Bindslev -Jensen C, Giménez-Arnau A, Bousquet PJ, et al. Unmet clinical needs in chronic spontaneous urticaria. A GA²LEN task force report. Allergy. 2011 Mar;66(3):317-30 24

25. Diagnosis of urticaria It is important to remember that not all possible causative factors need to be investigated in all patients and the first step in diagnosis is a thorough history: 25 Zuberbier T, Aberer W, Asero R, et al. The EAACI/GA²LEN/EDF/WAO guideline for the definition, classification, diagnosis and management of urticaria. The 2013 revision and update. Allergy 2014;69:868–87

26. Time of onset of disease Frequency and duration of wheals Diurnal variation Occurrence in relation to weekends, holidays, and foreign travel Shape , size, and distribution of wheals Associated angioedema Associated subjective symptoms of lesion, e.g. itch , pain Family and personal history regarding urticaria, atopy Previous or current allergies, infections, internal diseases, or other possible causes Psychosomatic and psychiatric diseases 11. Surgical implantations and events during surgery. 12 . Gastric/intestinal problems (stool, flatulence). 13 . Induction by physical agents or exercise. 14. Use of drugs (NSAIDs, injections, immunizations, hormones, laxatives, suppositories, ear and eye drops, and alternative remedies). 15 . Observed correlation to food. 16 . Relationship to the menstrual cycle. 17. Smoking habits. 18. Type of work. 19. Hobbies. 20. Stress (eustress and distress ). 21. Quality of life related to urticaria and emotional Impact. 22. Previous therapy and response to therapy. The first step in diagnosis is a thorough history Questions should be asked regarding the following items: Zuberbier T, Aberer W, Asero R, et al. The EAACI/GA²LEN/EDF/WAO guideline for the definition, classification, diagnosis and management of urticaria. The 2013 revision and update. Allergy 2014;69:868–87

27. 1. Zuberbier T, et al. Allergy 2009;64:1417‒26 Timing, frequency, duration of attacks Shape, size, distribution and associated symptoms of lesions Family and medical history, including allergies Correlation to any triggers, e.g. foods, exercise, drug use Work, hobbies, smoking habits and stress Previous therapy and response to treatment The first step in diagnosis is a thorough history Questions should be asked regarding the following items:

28. The second step of the diagnosis is the physical examination of the patient. This should include: A diagnostic provocation test including drug, food, and physical tests where it is indicated by history. Zuberbier T, Aberer W, Asero R, et al. The EAACI/GA²LEN/EDF/WAO guideline for the definition, classification, diagnosis and management of urticaria. The 2013 revision and update. Allergy 2014;69:868–87

29. Physical examination 1. Zuberbier T, et al. Allergy 2009;64:1417‒26 Tests to identify triggers: these should be performed where indicated by history to diagnose inducible urticaria subtypes 1

30. Routine diagnostic tests (recommended) Extended diagnostic program* (suggested based on history only) Cold urticaria Cold provocation and threshold test (ice cube, cold water, cold wind) Differential blood count and ESR or CRP cryoproteins rule out other diseases, especially infections Delayed pressure urticaria Pressure test and threshold test None Heat urticaria Heat provocation and threshold test None Solar urticaria UV and visible light of different wavelengths and threshold test Rule out other light-induced dermatoses Symptomatic dermographism Elicit dermographism and threshold test ( dermographometer ) Differential blood count, ESR or CRP Vibratory Angioedema Test with, for example, vortex None Aquagenic urticaria Wet cloths at body temperature applied for 20 min None Cholinergic urticaria Exercise and hot bath provocation None Contact urticaria Cutaneous provocation test. Skin tests with immediate readings, for example prick test None *Depending on suspected cause . Zuberbier T, Aberer W, Asero R, et al. Allergy 2014;69:868–87 Recommended diagnostic tests for frequent urticaria subtypes For Chronic inducible urticaria

31. Recommended diagnostic tests for frequent urticaria subtypes For CSU Routine diagnostic tests (recommended) Spontaneous urticaria Acute spontaneous urticaria None Chronic spontaneous urticaria Differential blood count and ESR or CRP Omission of suspected drugs (e.g. NSAIDs) Extended diagnostic programme* (suggested based on history only) for identification of underlying causes or eliciting factors and for ruling out possible differential diagnoses if indicated Spontaneous urticaria Acute spontaneous urticaria None ‡ Chronic spontaneous urticaria Infectious diseases (e.g. helicobacter Pylori) Type I allergy Functional autoantibodies Thyroid hormones and autoantibodies Skin tests including physical tests Pseudoallergen-free diet for 3 weeks Tryptase † Autologous serum skin test (ASST) Lesional skin biopsy *Depending on suspected cause; ‡ Unless strongly suggested by patient history, e.g. Allergy; † As indication of severe systemic disease. CRP = C-reactive protein; ESR = erythrocyte sedimentation rate; NSAIDs = nonsteroidal anti-inflammatory drugs. Zuberbier T, Aberer W, Asero R, et al. The EAACI/GA²LEN/EDF/WAO guideline for the definition, classification, diagnosis and management of urticaria. The 2013 revision and update. Allergy 2014;69:868–87 Please refer to the slide notes for further information.

32. Autologous Serum Skin Test (Auto-reactivity) A positive autologous serum skin test. . Sabroe RA, Greaves MW. Chronic idiopathic urticaria with functional autoantibodies: 12 years on. Br J Dermatol . 2006;154(5 ):813-9

33. ASST positivity and disease activity/severity Approximately one third of CSU patients show a positive response against their own serum in the autologous serum skin test (ASST) 1 autoantibodies against the high-affinity IgE receptor or against IgE itself can be detected in some of these patients 1 patients with autoimmune CSU appear to have more severe disease 2 more severe clinical features have been reported, including more wheals, larger wheal size, higher itch scores 3 – 5 longer duration of disease 5 –7 higher requirement for antihistamine medication 7 1. Maurer, M et al. Allergy 2011;66:317–30; 2. Kozel MMA, Sabroe RA. Drugs 2004;64:2515–36; 3. Sabroe RA, et al. J Am Acad Dermatol 1999;40:443–50; 4. Caproni M, et al. Acta Derm Venereol 2004;84:288–90; 5. Alyasin S, et al. South Med J 2011;104:111–5; 6. Konstantinou GN, et al. Allergy 2009;64:1256–68; 7. Staubach P, et al. Dermatology 2006;212:150–9

34. Should routine diagnostic measures be performed in acute urticaria? We recommend against any routine diagnostic measures in acute urticaria (strong recommendation/clinical consensus). 34 Zuberbier T, Aberer W, Asero R, et al. The EAACI/GA²LEN/EDF/WAO guideline for the definition, classification, diagnosis and management of urticaria. The 2013 revision and update. Allergy 2014;69:868–87

35. Should routine diagnostic measures be performed in chronic spontaneous urticaria? We recommend for only very limited routine diagnostic measures in chronic spontaneous urticaria (strong recommendation/ clinical consensus). 35 Zuberbier T, Aberer W, Asero R, et al. The EAACI/GA²LEN/EDF/WAO guideline for the definition, classification, diagnosis and management of urticaria. The 2013 revision and update. Allergy 2014;69:868–87

36. Diagnostic algorithm for patients presenting with wheals, angioedema , or both 36

37. 37 Zuberbier T, Aberer W, Asero R, et al. Allergy 2014;69:868–87

38. ACAAI/AAAAI Practice Parameter 2013 Limited non-specific laboratory evaluation CBC with diff ESR TSH BUN/Cr LFTs A thorough history and meticulous physical exam is essential for determining whether additional tests are appropriate: Skin biopsy Physical challenge tests C3, C4, and CH50 Functional autoantibody assay (for autoantibodies to Fc ε RI) and/or ASST Stool O&P UA Hepatitis B and C serologies CXR and/or other imaging studies ANA RF, Anti-CCP Cryoglobulin levels Serologic and/or skin testing for immediate hypersensitivity

39. WAO Guideline 2012 History/physical examTime of onset Frequency and duration of wheals Presence of diurnal variation Shape, size, and distribution of wheals Associated angioedema Family and personal history of urticaria Atopy Medications (NSAIDs, hormones, laxatives, immunizations) Observed correlation with food and stress Diagnostic studiesCBC /diff LFTs ESR, CRP Screening for thyroid autoimmunity "may be considered" (Anti- Tg , Anti-TPO) Physical urticaria testing Role of H. pylori is controversial, and the evidence is weak Skin biopsy may be needed to confirm urticarial vasculitis or Schnitzler syndrome

40. Kaplan CBC/diff - high eosinophil counts might trigger a stool examination for ova and parasites CRP or ESR TSH/FT4, anti-TPO, anti-TG antibodies - may be useful because so many CU patients are found to be hypothyroid and are then treated with a thyroid hormone Other tests Routine food allergy skin testing - not recommended ANA - not recommended in the absence of symptoms (other than urticaria ) that might suggest the presence of SLE Anti- IgE /anti- IgE receptor antibodies - of theoretical interest, but none of the treatment modalities distinguish patients with the antibodies from those without them Skin biopsy - when the diagnosis is not clear or when a vasculitis is suspected or at least needs to be ruled out Examples of circumstances where a skin biopsy should be performed would be the presence of fever, concomitant petechiae or palpable purpura , lesions that fade with bruising, individual lesions lasting >24 h (and certainly >36 h), or prominent arthralgia ANA, C3, C4, and C1q binding assay for circulating immune complexes and cryoglobulin determination would be included

41. Saini History/physical exam Duration of episodes and lesions appearance (photos) Medication/food history Identify physical triggers (significant in 20%) Consider infections Possible Lab Studies Basic series: CBC/diff, BMP, LFTs, UA Other testing guided by physical exam or history Extended: ESR, Anti- Tg , Anti-TPO, TSH, C3, C4 Consider "autoimmune" tests: basophil CD203c level or CU index Skin biopsy to exclude urticarial vasculitis or define cellular picture in atypical cases (elevated CRP or ESR, unresponsive to antihistamines, lesion duration >24h, painful rather than pruritic , petechial or purpuric changes, leave residual pigment changes). Peroni : Up to 40-60% of patients with UV may present only with wheals, therefore, a skin biopsy should be considered in all cases of otherwise clinically typical chronic urticaria , especially if the urticaria is resistant to antihistamines Procedure 3 mm punch biopsy from a  fresh  lesion. Patients receiving steroids may need to discontinue these medications to allow new lesions to form. Biopsy specimens should be submitted in formalin for routine H&E staining and in those patients in whom urticarial vasculitis is a strong consideration, in Michel’s media or freshly snap frozen for DIF microscopy.

42. Bernstein History/physical exam Evaluate for evidence of physical urticarias , dermatographism Initial testing CBC/diff ESR TSH LFTs UA Allergy skin testing is not indicated in the initial evaluation of urticaria Testing for refractory cases C4 Anti- Tg , Anti-TPO H. pylori antibodies Hepatitis panel Consider autologous serum skin test Consider skin biopsy if urticaria are atypical, not evanescent

43. Dreyfus Initial testing TSH, Anti- Tg CBC/diff SPEP LFTs Hepatitis titers H. pylori IgG , IgM and titers for other infectious illness - if suggested by history ANA and anti-DNA anti-bodies - if history or exam suggestive of vasculitis C1INH level and function, C2, C4 - if angioedema present Chromagranin A or urine catecholamines - if significant flushing, carcinoid features Tryptase - if significant component of anaphylaxis with urticaria , angioedema CXR and PFT - if associated respiratory symptoms such as cough, wheezing Total immunoglobulin levels, B/T cell subsets - if history suggestive of parasitic infection, chronic infection Pregnancy testing - if relevant age and sex Serum basophil activation or histamine release in vitro and/or autologous skin testing - not required but may be useful to confirm diagnosis

44. EAACI/WAO Guideline (2013) Routine diagnostic tests: CBC/diff ESR or CRP Omission of suspected drugs (e.g. NSAID) Extended diagnostic program for identification of eliciting factors and for ruling out possible differential diagnoses if indicated: Infectious diseases (e.g. Helicobacter pylori) Test for type I allergy - rare cause of chronic urticaria in patients with daily or almost daily symptoms, but must be considered in patients with intermittent symptoms Functional autoantibodies Thyroid hormones and autoantibodies Skin tests including physical tests Pseudoallergen -free diet for 3 weeks Tryptase level Autologous serum skin test Lesional skin biopsy

45. Diagnostic Approach for Children ( Boguniewicz ) Routine testing Allergy testing CBC/diff ESR LFTs TSH, FT4, anti- Tg , anti-TPO Extended testing for selected patients Hepatitis serology Complement levels ANA and specific autoimmune testing EBV testing Stool ova and parasites Skin biopsy if vasculitis or mastocytosis are suspected Children whose CU persists should have yearly re-evaluation to rule-out late onset autoimmune disease

46. Specialized Lab Testing for Urticaria CU Index  - patient's serum is added to healthy donor basophils and quantity of histamine release is measured. The reference range for a healthy non-CU population is <10. Values ≥10 indicate that basophils were stimulated by patient serum to release histamine (the larger the value the more histamine released). In one study, 23% of healthy controls vs. 57% of CU patients had a positive CU index Positive CU Index associated with more severe CIU Anti-FcεR1 (high affinity IgE receptor) IgG antibody - by Western blot, direct measurement of IgE receptor autoantibodies These antibodies may not correlate with disease activity and have been identified in other autoimmune diseases (even in the absence of urticaria ), including pemphigus vulgaris , SLE, dermatomyositis , and pemphigoid , suggesting that these antibodies may represent an epiphenomenon. Anti- IgE IgG antibody Basophil CD203c levels  - by flow cytometry , indirect measure of autoantibodies to IgE receptor which result in basophil activation. Anti-C1q antibody  - Patients with hypocoplementemic urticarial vasculitis syndrome (HUVS) usually have autoantibodies reactive with the collagen-like region of the C1q molecule, and can develop angioedema .

47. Additional Testing Notes D- dimer - elevated D- dimer may be a biomarker of antihistamine-resistant chronic urticaria ( Asero ) This subtype may respond to anticoagulation with tranexamic acid and low molecular weight heparin Wedi - careful search for at least infections with  H. pylori , strep, and perhaps also staph and yersinia should be included in the work-up of severely affected patients; our routine work-up includes: Helicobacter pylori monoclonal stool antigen test Serology for strep (ASO, anti- DNase B), staph ( antistaphylolysin ), yersinia ( IgA , IgG , immunoblot ). If an infection is identified, it should be appropriately treated and it should be checked whether eradication has been achieved. Initial evaluation for autoinflammatory syndromes (e.g. CAPS) should include: CBC/diff - to screen for neutrophilia CRP, ESR ANA - help rule out autoimmune disease UA - screen for proteinuria which suggests renal amyloidosis Serum amyloid A level - inflammation marker and screening parameter for amyloidosis Gene mutation analysis if specific diagnosis suspected (e.g. CAPS)

48. 49 Urticaria Burden

49. Impact of chronic spontaneous urticaria on the patients In addition to the classical clinical symptoms like pruritus, whealing and the occurrence of angioedema, many other factors are of major importance for patients with chronic spontaneous urticaria these include: The unpredictability of the attacks. Lack of quality sleep (due to pruritus). Fatigue caused by treatment. Side-effects. Cosmetic disfigurement. Quality of life Allergy 2011; 66: 317–330. 50

50. CSU adversely affects quality of life Many aspects of QoL are found to be reduced in patients with CSU, 1 with the presence of angioedema further impairing QoL scores 2 Mental status Tired Stressed Overwhelmed Anxious Daily living Physical activity Eating Concentrating Sleeping Leisure Restricted choice of clothing Limiting hobbies Avoiding sun exposure Self-perception Loneliness Conspicuousness Anxiety over the future Feeling unhygienic Treatment-induced restrictions Effect on every day activities Financial burden Discomfort Social functions Impact on relationships Impact on sexuality Chronic urticaria impacts Kang MJ, et al. Ann Dermatol 2009;21:226–9; Silvares MRC, et al. Rev Assoc Med Bras 2011;57:577− 82

51. Bold faces indicate low important items (overall impact <1.5). 67.11 2.59 1.74 Urticaria Interferes with Social relationship 84.21 2.73 2.29 Patients feel embarrassed by Urticaria signs 78.95 2.12 1.67 Difficulties in falling asleep 69.74 3.01 2.1 Urticaria Interferes with eating behavior Impact of chronic spontaneous urticaria on the patients Quality of life Baiardini I, Pasquali M, Braido F, Fumagalli F, Guerra L, et al. A new tool to evaluate the impact of chronic urticaria on quality of life: chronic urticaria quality of life questionnaire (CU- QoL ). Allergy. 2005;60(8 ):1073-8

52. Maurer M1, Weller K, Bindslev -Jensen C, Giménez-Arnau A, Bousquet PJ, et al. Unmet clinical needs in chronic spontaneous urticaria. A GA²LEN task force report. Allergy. 2011 Mar;66(3):317-30 53

53. Patients with CU feel similarly lacking in energy, socially isolated , and emotionally upset as the patients with heart disease Comparison of the NHP (part I) scores in patients with chronic urticaria (CU, n 5 134) and in patients with ischemic heart disease (IHD, n 5 98) awaiting coronary artery bypass grafting. (From O’Donnell BF, Lawlor F, Simpson J, et al. The impact of chronic urticaria on the quality of life. Br J Dermatol 1997;136(2):200; O’Donnell BF. Urticaria: Impact on Quality of Life and Economic Cost. Immunol Allergy Clin N Am 2014; 34: 89–104

54. S ocioeconomic burden The socioeconomic cost of Chronic urticaria is high in terms of direct medical costs and indirect costs, such as lost wages because of absences from work Direct costs include laboratory costs, outpatient visits, emergency department (ED)/hospital visits, and medication Indirect costs include income lost because of travel to outpatient visits and work absenteeism Based on a CSU prevalence of 0.04% among the US population, estimated mean total indirect and direct costs would be $244 million per year DeLong LK, et al. Arch Dermatol 2008;144:35− 9 $US $US

55. How to assess disease activity and quality of life? 56 Disease activity Quality of life UAS AAS CU-Q2ol AE- Qol Wheal Angioedema

56. Disease activity in spontaneous urticaria should be assessed using the UAS7 The UAS7 is a validated method for assessing disease activity A modification to the UAS7 , in which signs and symptoms are assessed two times per day, has also been validated Score Wheals Pruritus None None 1 Mild (<20 wheals/24 hours) Mild (present, but not annoying or troublesome) 2 Moderate (20–50 wheals/24 hours) Moderate (troublesome, but does not interfere with normal daily activity or sleep) 3 Intense (>50 wheals/24 hours or large confluent areas of wheals) Intense (severe pruritus, which is sufficiently troublesome to interfere with normal daily activity or sleep) Sum of score: 0–6 for each day is summarized over one week (maximum 42) Urticaria activity score Zuberbier T, Aberer W, Asero R, et al. The EAACI/GA²LEN/EDF/WAO guideline for the definition, classification, diagnosis and management of urticaria. The 2013 revision and update. Allergy 2014;69:868–87

57. Chronic Urticaria QoL Questionnaire (CU-Q 2 oL) CU-Q 2 oL is a relatively new tool based on the most frequent complaints of patients with CSU 1 It involves 23 questions scored using a Likert scale of five steps and shows good reliability for: 1,2 pruritus swelling impact on life activities sleep problems looks limits CU- Q 2 oL is more sensitive in comparison with other, non-disease specific QoL measures such as the DLQI 3 Weldon DR. Allergy Asthma Proc 2006;27:96 ‒9; Baiardini I, et al. Allergy. 2005;60:1073−8; Młynek A, et al. Allergy. 2009;64:927−36

58. Dermatology Life Quality Index (DLQI) DLQI was the first dermatology-specific tool to assess skin-related QoL 1,2 It is the most commonly used tool used to assess QoL of patients with dermatologic conditions, such as CU 2 DLQI measures 10 items on a four-point scale; the composite score can be calculated (range 0  30) 1 Both H, et al. J Investig Dermatol 2007;127:2726‒39; Weldon DR. Allergy Asthma Proc 2006;27:96 ‒9; Lennox RD, Leahy MJ. Ann Allergy Asthma Immunol 2004;93:142  6 Areas addressed by the DLQI include: 3 Lesions feel itchy, sore or painful Feelings of embarrassment Interference with shopping Lesions influencing decisions on clothing Social leisure affected Skin causing difficulty with sporting activities Difficulties with work or studying Problems with partner Sexual difficulties Treatment causing problems with home life

59. Angioedema Quality of life questionnaires The AE-QoL is a symptom-specific instrument for evaluating the effects of angioedema on health status AE-QoL = Angioedema Quality of Life Questionnaire. New in 2013 Zuberbier T, Aberer W, Asero R, et al. The EAACI/GA²LEN/EDF/WAO guideline for the definition, classification, diagnosis and management of urticaria. The 2013 revision and update. Allergy 2014;69:868–87 Weller K, et al. Allergy 2013;68:1185–92.

60. Which instrument should be used to measure QoL in urticaria ? We recommend using the validated CU-Q2oL and AE- QoL instruments for assessing QoL impairment and to monitor disease activity (strong recommendation/clinical consensus). 61 Zuberbier T, Aberer W, Asero R, et al. The EAACI/GA²LEN/EDF/WAO guideline for the definition, classification, diagnosis and management of urticaria. The 2013 revision and update. Allergy 2014;69:868–87

61. Treatment of Urticaria

62. Goal of treatment Should treatment aim at complete symptom control in urticaria? We recommend aiming for complete symptom control in urticaria as safely as possible (strong recommendation/clinical consensus following the WHO constitution in conformity with the Charter of the United Nations). Zuberbier T, Aberer W, Asero R, et al. The EAACI/GA²LEN/EDF/WAO guideline for the definition, classification, diagnosis and management of urticaria. The 2013 revision and update. Allergy 2014;69:868–87

63. Chronic urticaria is a mast cell-dependent disease and should be managed accordingly In CU, partly unknown stimuli cause mast cells to release their mediators leading to small (wheals) or larger and deeper (angioedema) edema of the skin The therapeutic approach is universal and based on the same principles as in other mast-cell dependent diseases: 1,2 Elimination/avoidance of the cause or trigger/stimulus Symptomatic pharmacological treatment by reducing mast cell mediator release and/or the effect of these mediators at the target organ Inducing tolerance Management algorithms for CU should take account of: 2 Variation in symptoms from one patient to another Need to step up or step down treatment Differences between easy-to-treat and refractory patients CU = chronic urticaria. 1. Zuberbier T, et al. EAACI/GA2LEN/EDF/WAO guideline: management of urticaria. Allergy 2009;64:1427–1443 2. Zuberbier T, Aberer W, Asero R, et al. The EAACI/GA²LEN/EDF/WAO guideline for the definition, classification, diagnosis and management of urticaria. The 2013 revision and update. Allergy 2014;69:868–87 New in the 2013 guidelines

64. Identification and elimination of the underlying cause and/or trigger Identification and subsequent elimination of the cause interrupts the pathogenic process and should lead to resolution of symptoms Urticaria and Angioedema. Zuberbier T, Grattan C, Maurer M, editors. Berlin: Springer-Verlag, 2010 Trigger Cause Mast cell- activating signal Mast cell activation Mast cell mediators Urticaria reaction causal symptomatic

65. Elimination or avoidance of the cause or trigger/stimulus requires an exact diagnosis Drugs When such agents are suspected in the course of diagnosis, they should be omitted entirely or substituted by another class of agents if indispensable Drugs causing non-allergic hypersensitivity reactions (e.g. NSAIDs) cannot only elicit, but can also aggravate pre-existing CSU, so that elimination in the latter case will only improve symptoms in some patients Physical stimuli Avoidance is desirable but not always simple Eradication of infections and treatment of inflammatory processes CSU is often associated with inflammatory or infectious diseases Infections should be treated appropriately, but it is unclear whether they have significant causative role Reduction of functional autoantibodies There is little experience in the reduction of functional autoantibodies with plasmaphoresis in CSU Such treatment should be reserved for patients unresponsive to all other forms of treatment Dietary management IgE-mediated food allergy is rarely the underlying cause of CSU Pseudoallergic reactions to foods have been seen in some patients with CSU In such cases, diet low in pseudoallergens should be implemented for ≥ 3–6 months CU = chronic urticaria; CSU = chronic spontaneous urticaria; NSAID = non-steroidal anti-inflammatory drug. Zuberbier T, Aberer W, Asero R, et al. The EAACI/GA²LEN/EDF/WAO guideline for the definition, classification, diagnosis and management of urticaria. The 2013 revision and update. Allergy 2014;69:868–87 Unchanged since 2009

66. Induction of tolerance may be useful in some urticaria subtypes Inducing tolerance may be effective in cold, cholinergic and solar urticaria Tolerance only lasts for a few days, so consistent daily exposure is required This may not be tolerated by patients (e.g. in the case of cold baths for cold urticaria) Unchanged since 2009 Zuberbier T, Aberer W, Asero R, et al. The EAACI/GA²LEN/EDF/WAO guideline for the definition, classification, diagnosis and management of urticaria. The 2013 revision and update. Allergy 2014;69:868–87

67. Trigger Cause Mast cell- activating signal Mast cell activation Mast cell mediators Urticaria reaction symptomatic Therapeutic strategies targeting mast cell mediators When the cause of urticaria cannot be identified or eliminated, treatment is targeted at mast cell mediators Urticaria and Angioedema. Zuberbier T, Grattan C, Maurer M, editors. Berlin: Springer-Verlag, 2010 causal

68. Guidelines R ecommendations Toward Urticaria Management *The order of third-line treatments does not reflect preference. Zuberbier T, Aberer W, Asero R, et al. The EAACI/GA²LEN/EDF/WAO guideline for the definition, classification, diagnosis and management of urticaria. The 2013 revision and update. Allergy 2014;69:868–87 First line: Modern second-generation antihistamines Second line: Increase dosage up to fourfold of modern second-generation antihistamines Third line : Add on to second-line *: omalizumab or ciclosporin A or montelukast Short course ( maximum 10 days) of corticosteroids may also be used at all times if exacerbations demand this If symptoms persist after 2 weeks If symptoms persist after 1–4 further weeks Revised in the 2013 guidelines 69

69. Continuous treatment with H1-antihistamines is central to the management of CU Many symptoms of urticaria are mediated primarily by histamine Histamine H 1 receptors are located on endothelial cells and sensory nerves H 1 -antihistamines stabilize these receptors in an inactive state In some cases, other mast cell mediators (PAF, leukotrienes, cytokines) are also involved and a pronounced cellular infiltrate including basophils, lymphocytes and eosinophils may be observed Such cases may respond to a brief course of corticosteroids and may be relatively refractory to H 1 -antihistamines Use of first-generation (sedating) antihistamines is not recommended for routine management of urticaria Modern second-generation H 1 -antihistamines should be considered as the first-line treatment for urticaria Up-dosing (up to 4× licensed dose) is the second-line option PAF = platelet activating factor. New in 2013 No change No change Zuberbier T, Aberer W, Asero R, et al. The EAACI/GA²LEN/EDF/WAO guideline for the definition, classification, diagnosis and management of urticaria. The 2013 revision and update. Allergy 2014;69:868–87

70. 71 Zuberbier T, Aberer W, Asero R, et al. The EAACI/GA²LEN/EDF/WAO guideline for the definition, classification, diagnosis and management of urticaria. The 2013 revision and update. Allergy 2014;69:868–87

71. 72 Up to 50% of CSU patients have an inadequate response to H1-antihistamines at licensed doses. 1,2 1. Maurer M, et al. Allergy 2011;66:317–30. 2 . Weller K, et al. J Eur Acad Dermatol venereol 2013;27:43-50 How do you help your H1-antihistamines refractory patients?

72. Ciclosporin A has a moderate, direct effect on mast cell mediator release Shown to be effective in double-blind placebo-controlled studies Efficacy in combination with modern second generation H 1 -antihistamines has been shown in placebo-controlled trials and open controlled trials Not recommended as standard treatment due to high incidence of adverse effects Recommended only use in severe disease refractory to any dose of antihistamine Information on ciclosporin A and corticosteroids is similar to that in the 2009 guidelines; Zuberbier T, Aberer W, Asero R, et al. The EAACI/GA²LEN/EDF/WAO guideline for the definition, classification, diagnosis and management of urticaria. The 2013 revision and update. Allergy 2014;69:868–87 Similar to 2009 Treatment of antihistamine-refractory patients : Ciclosporin A

73. LTRAs are associated with a low level of evidence for efficacy in urticaria The best evidence is for montelukast In urticaria, topical corticosteroids are not helpful (with the possible exception of pressure urticaria on the soles of the feet [low evidence]) If systemic corticosteroids are used, doses between 20–50 mg/day are required Adverse effects occur during on long-term use There is a strong recommendation against long-term use of corticosteroids outside specialist clinics In many countries, corticosteroids are not licenced for use in urticaria D escription of LTRAs has been changed since 2009 and now notes that the best evidence is for montelukast. LTRA = leukotriene receptor antagonist. Zuberbier T, Aberer W, Asero R, et al. The EAACI/GA²LEN/EDF/WAO guideline for the definition, classification, diagnosis and management of urticaria. The 2013 revision and update. Allergy 2014;69:868–87 Revised Similar to 2009 Treatment of antihistamine-refractory patients : LTRAs and corticosteroids

74. Omalizumab (anti- IgE ) has now been shown to be very effective in the treatment for CSU , both in case reports and case series as well as in double-blind placebo-controlled studies in antihistamine refractory selected patients. 75 Treatment of antihistamine-refractory patients : Omalizumab Zuberbier T, Aberer W, Asero R, et al. The EAACI/GA²LEN/EDF/WAO guideline for the definition, classification, diagnosis and management of urticaria. The 2013 revision and update. Allergy 2014;69:868–87 Revised

75. Treatment of antihistamine-refractory patients: Other treatment options H₂-antagonists and dapsone are no longer included as recommended treatment options The 2009 version of the guidelines included them as fourth-line options, but the evidence is too low to maintain the recommendation Sulfasalazine , methotrexate, interferon, plasmaphoresis , phototherapy and IVIGs are supported only by trials of low quality and case series Antagonists of TNF α and IVIG have been used successfully in case reports These options are recommended only for used in specialized centres as a last resort (i.e ., anti-TNF α for delayed pressure urticaria and IVIG for CSU) Phototherapy has been used successfully in mastocytosis and is helpful in treatment-resistant patients with this condition For the treatment of CSU and symptomatic dermographism, UV-A, PUVA and UV-B (nb-UVB) treatment for 1–3 months can be added to antihistamine treatment CSU = chronic spontaneous urticaria; IVIG = intravenous immunoglobulin; nb-UVB = narrowband ultraviolet B; PUVA = psoralen and ultraviolet A; TNF α = tumour necrosis factor alpha; UV = ultraviolet. Zuberbier T, Aberer W, Asero R, et al. The EAACI/GA²LEN/EDF/WAO guideline for the definition, classification, diagnosis and management of urticaria. The 2013 revision and update. Allergy 2014;69:868–87 Similar to 2009 Revised

76. Maurer.M , Magerl M, Metz M, Zuberbier.T , et al.Revisions to the international guidelines on the diagnosis and therapy of chronic urticaria. Journal of German Society of Dermatology. 2013. DOI: 10.1111/ddg.12194

77. 78

78. 79 Thank You

79. 80

80. Diagnostic Approach

81. ACAAI/AAAAI Practice Parameter 2013 Limited non-specific laboratory evaluation CBC with diff ESR TSH BUN/Cr LFTs A thorough history and meticulous physical exam is essential for determining whether additional tests are appropriate: Skin biopsy Physical challenge tests C3, C4, and CH50 Functional autoantibody assay (for autoantibodies to Fc ε RI) and/or ASST Stool O&P UA Hepatitis B and C serologies CXR and/or other imaging studies ANA RF, Anti-CCP Cryoglobulin levels Serologic and/or skin testing for immediate hypersensitivity

82. WAO Guideline 2012 History/physical examTime of onset Frequency and duration of wheals Presence of diurnal variation Shape, size, and distribution of wheals Associated angioedema Family and personal history of urticaria Atopy Medications (NSAIDs, hormones, laxatives, immunizations) Observed correlation with food and stress Diagnostic studiesCBC /diff LFTs ESR, CRP Screening for thyroid autoimmunity "may be considered" (Anti- Tg , Anti-TPO) Physical urticaria testing Role of H. pylori is controversial, and the evidence is weak Skin biopsy may be needed to confirm urticarial vasculitis or Schnitzler syndrome

83. Kaplan CBC/diff - high eosinophil counts might trigger a stool examination for ova and parasites CRP or ESR TSH/FT4, anti-TPO, anti-TG antibodies - may be useful because so many CU patients are found to be hypothyroid and are then treated with a thyroid hormone Other tests Routine food allergy skin testing - not recommended ANA - not recommended in the absence of symptoms (other than urticaria ) that might suggest the presence of SLE Anti- IgE /anti- IgE receptor antibodies - of theoretical interest, but none of the treatment modalities distinguish patients with the antibodies from those without them Skin biopsy - when the diagnosis is not clear or when a vasculitis is suspected or at least needs to be ruled out Examples of circumstances where a skin biopsy should be performed would be the presence of fever, concomitant petechiae or palpable purpura , lesions that fade with bruising, individual lesions lasting >24 h (and certainly >36 h), or prominent arthralgia ANA, C3, C4, and C1q binding assay for circulating immune complexes and cryoglobulin determination would be included

84. Saini History/physical exam Duration of episodes and lesions appearance (photos) Medication/food history Identify physical triggers (significant in 20%) Consider infections Possible Lab Studies Basic series: CBC/diff, BMP, LFTs, UA Other testing guided by physical exam or history Extended: ESR, Anti- Tg , Anti-TPO, TSH, C3, C4 Consider "autoimmune" tests: basophil CD203c level or CU index Skin biopsy to exclude urticarial vasculitis or define cellular picture in atypical cases (elevated CRP or ESR, unresponsive to antihistamines, lesion duration >24h, painful rather than pruritic , petechial or purpuric changes, leave residual pigment changes). Peroni : Up to 40-60% of patients with UV may present only with wheals, therefore, a skin biopsy should be considered in all cases of otherwise clinically typical chronic urticaria , especially if the urticaria is resistant to antihistamines Procedure 3 mm punch biopsy from a  fresh  lesion. Patients receiving steroids may need to discontinue these medications to allow new lesions to form. Biopsy specimens should be submitted in formalin for routine H&E staining and in those patients in whom urticarial vasculitis is a strong consideration, in Michel’s media or freshly snap frozen for DIF microscopy.

85. Bernstein History/physical exam Evaluate for evidence of physical urticarias , dermatographism Initial testing CBC/diff ESR TSH LFTs UA Allergy skin testing is not indicated in the initial evaluation of urticaria Testing for refractory cases C4 Anti- Tg , Anti-TPO H. pylori antibodies Hepatitis panel Consider autologous serum skin test Consider skin biopsy if urticaria are atypical, not evanescent

86. Dreyfus Initial testing TSH, Anti- Tg CBC/diff SPEP LFTs Hepatitis titers H. pylori IgG , IgM and titers for other infectious illness - if suggested by history ANA and anti-DNA anti-bodies - if history or exam suggestive of vasculitis C1INH level and function, C2, C4 - if angioedema present Chromagranin A or urine catecholamines - if significant flushing, carcinoid features Tryptase - if significant component of anaphylaxis with urticaria , angioedema CXR and PFT - if associated respiratory symptoms such as cough, wheezing Total immunoglobulin levels, B/T cell subsets - if history suggestive of parasitic infection, chronic infection Pregnancy testing - if relevant age and sex Serum basophil activation or histamine release in vitro and/or autologous skin testing - not required but may be useful to confirm diagnosis

87. EAACI/WAO Guideline (2013) Routine diagnostic tests: CBC/diff ESR or CRP Omission of suspected drugs (e.g. NSAID) Extended diagnostic program for identification of eliciting factors and for ruling out possible differential diagnoses if indicated: Infectious diseases (e.g. Helicobacter pylori) Test for type I allergy - rare cause of chronic urticaria in patients with daily or almost daily symptoms, but must be considered in patients with intermittent symptoms Functional autoantibodies Thyroid hormones and autoantibodies Skin tests including physical tests Pseudoallergen -free diet for 3 weeks Tryptase level Autologous serum skin test Lesional skin biopsy

88. Diagnostic Approach for Children ( Boguniewicz ) Routine testing Allergy testing CBC/diff ESR LFTs TSH, FT4, anti- Tg , anti-TPO Extended testing for selected patients Hepatitis serology Complement levels ANA and specific autoimmune testing EBV testing Stool ova and parasites Skin biopsy if vasculitis or mastocytosis are suspected Children whose CU persists should have yearly re-evaluation to rule-out late onset autoimmune disease

89. Specialized Lab Testing for Urticaria CU Index  - patient's serum is added to healthy donor basophils and quantity of histamine release is measured. The reference range for a healthy non-CU population is <10. Values ≥10 indicate that basophils were stimulated by patient serum to release histamine (the larger the value the more histamine released). In one study, 23% of healthy controls vs. 57% of CU patients had a positive CU index Positive CU Index associated with more severe CIU Anti-FcεR1 (high affinity IgE receptor) IgG antibody - by Western blot, direct measurement of IgE receptor autoantibodies These antibodies may not correlate with disease activity and have been identified in other autoimmune diseases (even in the absence of urticaria ), including pemphigus vulgaris , SLE, dermatomyositis , and pemphigoid , suggesting that these antibodies may represent an epiphenomenon. Anti- IgE IgG antibody Basophil CD203c levels  - by flow cytometry , indirect measure of autoantibodies to IgE receptor which result in basophil activation. Anti-C1q antibody  - Patients with hypocoplementemic urticarial vasculitis syndrome (HUVS) usually have autoantibodies reactive with the collagen-like region of the C1q molecule, and can develop angioedema .

90. Additional Testing Notes D- dimer - elevated D- dimer may be a biomarker of antihistamine-resistant chronic urticaria ( Asero ) This subtype may respond to anticoagulation with tranexamic acid and low molecular weight heparin Wedi - careful search for at least infections with  H. pylori , strep, and perhaps also staph and yersinia should be included in the work-up of severely affected patients; our routine work-up includes: Helicobacter pylori monoclonal stool antigen test Serology for strep (ASO, anti- DNase B), staph ( antistaphylolysin ), yersinia ( IgA , IgG , immunoblot ). If an infection is identified, it should be appropriately treated and it should be checked whether eradication has been achieved. Initial evaluation for autoinflammatory syndromes (e.g. CAPS) should include: CBC/diff - to screen for neutrophilia CRP, ESR ANA - help rule out autoimmune disease UA - screen for proteinuria which suggests renal amyloidosis Serum amyloid A level - inflammation marker and screening parameter for amyloidosis Gene mutation analysis if specific diagnosis suspected (e.g. CAPS)

91. 93

92. Chronic infection and chronic urticaria Chronic infection — in most cases it is not clear whether the two processes are related, occur simultaneously by chance, or are influenced by medications The following infections reported to be associated with urticaria , with improvement after infection resolved: Parasitic Ascaris ,  Ancylostoma ,  Strongyloides ,  Filaria ,  Giardia lamblia ,   Entamoeba spp ,  Blastocystis spp ,  Echinococcus ,  Schistosoma ,  Trichinella , Toxocara , and  Fasciola Anisakis simplex  (a sea fish nematode) has been reported as possible cause of recurrent acute urticaria in areas of the world where uncooked fish is eaten frequently Bacterial:  H. pylori,  Streptococcus spp , Staphylococcus spp , Yersinia enterocolitica , Mycoplasma pneumonia In a meta-analysis, rate of CU remission when  H. pylori  was eradicated was 30.9% vs. 21.7% when not Viral: hepatitis C, CMV,  EBV , norovirus , parvovirus B19 Unspecified organisms: tonsillitis, sinusitis, dental infection, UTI Fungal: The existence of an ‘id’ reaction with urticaria secondary to a fungal infection is no longer considered tenable (Kaplan)

93. Malignancy and chronic urticaria Lymphoproliferative disease/malignancy — rarely have simple urticaria , typically have lesions consistent with  urticarial vasculitis , and present with other systemic symptoms Schnitzler's syndrome - onset in 50's, monoclonal IgM or IgG gammopathy with recurrent fever, weight loss, bone pain, myalgias / arthralgias , lymphadenopathy , and non- pruritc urticaria that may become pruritic . May be due to circulating immune complexes and complement activation, anakinra (IL-1R antagonist) effective. Also reported with B-cell lymphomas, Hodgkins , CML, lung/colorectal/liver carcinomas

94. Back up slides about Role of O malizumab in CSU 97

95. 98 Emerging a New Standard of Care for Refractory CSU Patients Xolair ® ( omalizumab ) Treatment of antihistamine-refractory patients (cont’d)

96. How do you help your refractory CSU patients when…? 99 Up to 50% of CSU patients have an inadequate response to H1-antihistamines at licensed doses. 1,2 Beyond Omalizumab, there are no other licensed treatment options. 1 Until now, there has been no standard of care for these refractory CSU patients. 1 1. Maurer M, et al. Allergy 2011;66:317–30. 2 . Weller K, et al. J Eur Acad Dermatol venereol 2013;27:43-50

97. Now you can change the lives of refractory CSU patients with Omalizumab 100

98. Introduction to Omalizumab Xolair ® ( omalizumab ) is a recombinant DNA-derived humanized monoclonal antibody that selectively binds to human immunoglobulin E ( lgE ). Xolair ® 300mg (2x150mg/4 weeks) injection is indicated for adults and adolescents (12 years of age and above) with chronic spontaneous urticaria refractory to standard of care . Xolair BPI, 2014 In Allergic Asthma: Xolair has been listed in the Egyptian market for more than 6 years, and indicated for adults and children (6 years of age and above) with moderate to severe persistent allergic asthma whose symptoms are inadequately controlled with inhaled corticosteroids (ICS). Xolair has been shown to decrease the incidence of asthma exacerbations in these patients. Safety and efficacy have not been established in other allergic conditions.

99. Apart from reducing free IgE levels, the additional mechanisms by which omalizumab works in patients with CSU remains unclear . Reports describe patients with CSU as having abnormal basophil function, including: 1 D ecreased responsiveness to stimuli acting through the IgE receptor (50% of patients), B lood basopenia , and R ecruitment of basophils into skin lesions . With successful therapy, blood basopenia and FcεRI function began to return to normal levels. 1 102 1. Vonakis BM, Saini SS. New concepts in chronic urticaria. Curr Opin Immunol 2008;20:709-16 . Omalizumab Mode of Action:

100. In previous studies, omalizumab reduced free IgE levels within hours after administration and down regulates Fc ε RI on blood basophils within 2 weeks; A study of human cutaneous mast cells indicates a down regulatory effect in 3 to 4 weeks. 1,2 However , in individual patients the time course of symptom control does not necessarily follow these parameters . 103 1 . Beck LA, Marcotte GV, MacGlashan D, Togias A, Saini S. Omalizumab-induced reductions in mast cell Fc ε RI expression and function. J Allergy Clin Immunol 2004;114:527-30 . 2. Gomez G, Jogie-Brahim S, Shima M, Schwartz LB. Omalizumab reverses the phenotypic and functional effects of IgE -enhanced Fc ε RI on human skin mast cells . J Immunol 2007;179:1353-61. Omalizumab Mode of Action

101. Phase III Programme in CSU Patients (12−75 years) with CSU refractory to standard of care ASTERIA I (Q4881g) ASTERIA II (Q4882g) GLACIAL (Q4883g) Background therapy throughout treatment period † H 1 -antihistamines (approved doses) H 1 -antihistamines (approved doses) H 1 -antihistamines up to 4x approved dose plus H 2 -blocker / LTRA Presence of itch/hives prior to enrolment ≥8 Weeks ≥8 Weeks >6 weeks UAS7 ≥16 for at least 4 out of the 7 days in the week prior to randomization Weekly itch score ≥8 for the 7 days prior to randomization † Patients must have been on background therapy for at least 3 consecutive days immediately prior to Day -14 screening visit 104 16 week follow-up ASTERIA I − 24 week treatment 75 mg/150 mg/300 mg /Placebo 16 week follow-up GLACIAL − 24 week treatment 300 mg/Placebo 16 week follow-up = monthly flat dosing = primary endpoint (Week 12) ASTERIA II − 12 week treatment 75 mg/150 mg/300 mg/Placebo – 2 0 4 8 12 16 20 24 28 32 36 40 2-week screening period Study Design – ASTERIA I, ASTERIA II, Glacial

102. Xolair ® Clinical Trails 105 6 SC Xolair injections over 24 weeks ASTERIA I ASTERIA II GLACIAL Xolair ® 300 mg vs. Xolair ® 150 mg vs. Xolair ® 75 mg vs. placebo (1:1:1:1) Moderate-to-severe CSU Follow-up period: 16 weeks Xolair ® 300 mg vs. placebo (3:1) 318 patients 322 patients 335 patients 3 SC Xolair injections over 12 weeks 6 SC Xolair injections over 24 weeks Patients continued to receive stable doses of their prerandomization background therapy (therapies) throughout the treatment period

103. Patient baseline demographics ( mITT population): ASTERIA II and GLACIAL* *Please refer to the manuscripts for a full list of patient baseline demographic data; Data are means (SDs) unless otherwise stated; † Measured in 78 patients in the placebo group. CIU=chronic idiopathic urticaria ; CSU=chronic spontaneous urticaria ; DLQI=Dermatology Life Quality Index; mITT =modified intention to treat; OMA= omalizumab ; SD=standard deviation; UAS= urticaria activity score; UAS7=weekly urticaria activity score. Maurer M, et al. N Engl J Med 2013; Kaplan A, et al. J Allergy Clin Immunol 2013. Characteristic ASTERIA II 1 GLACIAL 2 Placebo (n=79) OMA 75 mg (n=82) OMA 150 mg (n=82) OMA 300 mg (n=79) Placebo (n=83) OMA 300 mg (n=252) Age, years 43.1  12.5 39.7  15.0 43.0  13.2 44.3  13.7 44.3  14.7 42.7  13.9 Female sex, no. (%) 55 (70) 61 (74) 65 (79) 63 (80) 55 (66.3) 186 (73.8) Race (white), no. (%) 70 (89) 64 (78) 70 (85) 68 (86) 75 (90.4) 223 (88.5) Body mass index (kg/m 2 ) 30.0  7.7 30.2  7.7 30.0  7.3 29.0  6.3 31.0  9.6 29.4  7.1 Time since diagnosis of CSU, years Mean Median 7.2  10.7 3.3 5.3  7.1 2.5 7.2  8.9 3.9 6.1  7.3 3.5 8.8  11.2 4.1 7.0  8.8 3.4 No. of previous CSU medications 4.4  2.9 4.1  2.1 4.5  3.2 4.3  2.5 6.4  2.9 5.9  2.5 In-clinic UAS 5.3  0.7 5.4  0.8 5.3  0.7 5.3  0.7 5.2  0.8 5.2  0.8 UAS7 31.0  6.6 30.7  6.9 31.4  7.0 29.5  6.9 30.2  6.7 31.2  6.6 Weekly itch severity score 14.0  3.4 14.0  3.7 14.2  4.1 13.7  3.5 13.8  3.6 14.0  3.6 Weekly no. of hives score 17.0  4.2 16.8  4.2 17.1  4.1 15.8  4.6 16.4  4.6 17.1  4.2 Overall DLQI score 12.6  5.9 † 12.6  6.5 13.0  6.1 12.7  6.4   Presence of angioedema , no (%) 30 (38) 31 (38) 38 (46) 32 (41) 41 (49.4) 137 (54.4)

104. O bjectives of the 3 clinical trials 107 Evaluation of the efficacy of Omalizumab compared with placebo in patients who remained symptomatic despite H1-antihistamine therapy (at licensed doses.) Safety and tolerability were evaluated as secondary objectives. GLACIAL ASTERIA I and ASTERIA II Evaluation of the safety of Omalizumab compared with placebo in CSU patients who remained symptomatic despite treatment with H1-antihistamines at up to 4 times the approved dose plus H2-antihistamines, leukotriene receptor antagonists, or both . Efficacy was assessed as a secondary objective.

105. Primary and secondary endpoints Asteria I N=318 Asteria II N=322 Glacial N=335 Primary endpoint Change from baseline to Week 12 in weekly Itch Severity Score (ISS) Safety Secondary endpoints At Week 12: Change from baseline in UAS7 Change from baseline in weekly # of hives score Time to MID (≥5 points) response in weekly ISS Proportion of patients with UAS7  ≤ 6 Proportion of weekly ISS MID responders Change from baseline in weekly size of largest hive score Change from baseline in DLQI Proportion of angioedema‑free days from Week 4 to Week 12 of therapy Proportion of Complete Responders (UAS7=0)* Same as Asteria I and Asteria II primary and secondary endpoints *Exploratory endpoint in Asteria II. DLQI, Dermatology Life Quality Index, UAS7, urticaria activity score over 7 days. MID: minimal important difference

106. Summary for results of Omalizumab 300 mg vs Placebo in Phase III Programme in CSU

107. 110 71% reduction in itch with Omalizumab 300 mg vs baseline at 12 weeks 1 Asteria II Patients were receiving background treatment of non-sedating H1-antihistamines at approved doses; all p-values are relative to the placebo group; data represent the modified intention-to-treat ( mITT ) population; ISS, itch severity score 1. Maurer M, et al. N Engl J Med 2013;368:924–35. Omalizumab 300 mg Placebo 71%

108. 111 Omalizumab 300 mg Placebo Patients were receiving background treatment of non-sedating H1-antihistamines at approved doses; all p-values are relative to the placebo group; data represent the modified intention-to-treat ( mITT ) population; ISS, itch severity score 67% reduction in itch with Omalizumab 300 mg vs baseline at 12 weeks 1,2 Asteria I 1. Saini SS, et al. Ann Allergy Asthma Immunol 2013;111 (Suppl. 5):A18. 2 . Rosén K, et al. Allergy 2013;68 (Suppl. 97):259. 67%

109. 62% reduction in itch with Omalizumab 300 mg vs baseline at 12 weeks 1 112 Glacial Patients were receiving background treatment of non-sedating H1-antihistamines (up to 4x the approved dose) plus H2-antihistamines and/or leukotriene-receptor antagonists; all p-values are relative to the placebo group; data represent the modified intention-to-treat ( mITT ) population; ISS, itch severity score 1 . Kaplan A, et al. J Allergy Clin Immunol 2013;132:101–9 29% Omalizumab 300 mg Placebo 62%

110. Rapid itch reduction after the 1st dose with O malizumab 300 mg 1 113 Asteria I 1. Saini SS, et al. Ann Allergy Asthma Immunol 2013;111 (Suppl. 5):A18. 2 . Rosén K, et al. Allergy 2013;68 (Suppl. 97): 259. 3. Mathias SD, et al. Ann Allergy Asthma Immunol 2012;108:20–4 * 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 3 ** Time to achieve minimally important difference in weekly itch severity score was 1 week with Omalizumab. Patients were receiving background treatment of non-sedating H1-antihistamines at approved doses; adapted from Novartis/Genentech , data on file (Q4881g); data represent the modified intention-to-treat ( mITT ) population; ISS, itch severity score P<0.0001 for the comparison with placebo at week 12 Denotes treatment administration

111. 114 Asteria II * 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 3 ** Time to achieve minimally important difference in weekly itch severity score was 1 week with Omalizumab. Patients were receiving background treatment of non-sedating H1-antihistamines at approved doses; adapted from Novartis/Genentech , data on file (Q4881g); data represent the modified intention-to-treat ( mITT ) population; ISS, itch severity score P<0.0001 for the comparison with placebo at week 12 1. Maurer M, et al. N Engl J Med 2013;368:924–35. Rapid itch reduction after the 1st dose with Omalizumab 300 mg 1 Rapid reduction** Itch re-emerges after end of treatment *

112. 115 Rapid itch reduction after the 1st dose with Omalizumab 300 mg 2 * 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. D ata represent the modified intention-to-treat ( mITT ) population; ISS, itch severity score. P <.001 for the comparison with placebo at week 12 Mean change from baseline in weekly ISS by study week (baseline observation carried forward method , modified intention-to-treat population). Itch re-emerges after end of treatment * Rapid reduction** ................................. ...... Discontinuation of O malizumab adapted from Kaplan A, et al . 2013

113. Omalizumab increased the proportion of patients who were itch-free and hive-free (UAS7=0) at Week 12 vs. placebo* The mean percentage of patients who were free of itch and hives (UAS7=0) was significantly greater in the omalizumab 150 mg (ASTERIA II) and 300 mg groups (ASTERIA II and GLACIAL) vs. placebo ASTERIA II ( mITT population) 1 GLACIAL ( mITT population) 2 10 20 50 Proportion (%) of patients with UAS7=0 at Week 12 22.0 44.3 40 30 Maurer M, et al. N Engl J Med 2013; Kaplan A, et al. J Allergy Clin Immunol 2013. *Post hoc analysis in ASTERIA II / secondary endpoint in GLACIAL. mITT =modified intention-to-treat; OMA= omalizumab ; UAS7=weekly urticaria activity score. p<0.001 OMA 300 mg Placebo Placebo OMA 75 mg OMA 150 mg OMA 300 mg

114. 44% of patients were itch- and hive-free with Omalizumab 300 mg at 12 weeks 1 117 Omalizumab 300 mg Placebo Patients were receiving background treatment of non-sedating H1-antihistamines at approved doses; adapted from Maurer M, et al . 2013; data represent the modified intention-to-treat ( mITT ) population; UAS7, urticaria activity score over 7 days 1. Maurer M, et al. N Engl J Med 2013;368:924–35. Asteria II 4 4%

115. Omalizumab significantly increased the proportion of patients who were well controlled ( UAS7≤6) at Week 12* A significantly higher proportion of patients in the omalizumab 150 mg (ASTERIA II) and 300 mg groups (ASTERIA II and GLACIAL) had symptoms which were well-controlled (UAS7≤6) vs. placebo 15 30 45 60 75 90 Proportion (%) of patients with UAS7≤6 at Week 12 42.7 65.8 p<0.05 p<0.05 *Secondary endpoint in ASTERIA II and GLACIAL. mITT =modified intention-to-treat; OMA= omalizumab ; UAS7=weekly urticaria activity score. ASTERIA II ( mITT population) 1 GLACIAL ( mITT population) 2 Maurer M, et al. N Engl J Med 2013; Kaplan A, et al. J Allergy Clin Immunol 2013. p<0.001 OMA 300 mg Placebo Placebo OMA 75 mg OMA 150 mg OMA 300 mg

116. 66% of patients achieved UAS7≤6 with Omalizumab 300 mg at 12 weeks 1 119 Asteria II 1. Maurer M, et al. N Engl J Med 2013;368:924–35. 6 6%* Omalizumab 300 mg Placebo * p<0.0001 relative to placebo group Patients were receiving background treatment of non-sedating H1-antihistamines at approved doses; adapted from Maurer M, et al. 2013; data represent the modified intention-to-treat ( mITT ) population; UAS7, urticaria activity score over 7 days.

117. Omalizumab significantly improved QoL (DLQI) * at Week 12 vs. placebo *Secondary endpoint in ASTERIA II and GLACIAL. DLQI=Dermatology Life Quality Index; mITT=modified intention-to-treat population; OMA= omalizumab ; QoL =quality-of-life. Maurer M, et al. N Engl J Med 2013; Kaplan A, et al. J Allergy Clin Immunol 2013. –15 –10 –5 –8.3 –10.2 Change from baseline in DLQI score at Week 12 p<0.001 p=0.02 ASTERIA II ( mITT population) 1 GLACIAL ( mITT population) 2 Significant improvements in QoL (measured using DLQI) seen with omalizumab 150 mg (ASTERIA II) and 300 mg (ASTERIA II and GLACIAL) vs. placebo Placebo OMA 75 mg OMA 150 mg OMA 300 mg OMA 300 mg Placebo p<0.001

118. 80% reduction in DLQI score with Omalizumab 300 mg vs baseline at 12 weeks 1 121 Omalizumab 300 mg Placebo 48% 80% Asteria II Patients were receiving background treatment of non-sedating H1-antihistamines at approved doses; all p-values are relative to the placebo group; data represent the modified intention-to-treat ( mITT ) population; DLQI, Dermatology Life Quality Index. Maurer M, et al. N Engl J Med 2013;368:924–35 .

119. Omalizumab significantly improved angioedema-free days during Weeks 4–12 vs. placebo * Significantly greater proportion of angioedema-free days between Weeks 4–12 seen with omalizumab 300 mg (ASTERIA II and GLACIAL) vs. placebo Maurer M, et al. N Engl J Med 2013; Kaplan A, et al. J Allergy Clin Immunol 2013. ASTERIA II ( mITT population) 1 GLACIAL ( mITT population) 2 *Secondary endpoint in ASTERIA II and GLACIAL. mITT =modified intention-to-treat population; OMA= omalizumab . 20 40 60 80 100 Proportion (%) of angioedema -free days over Weeks 4–12 91.6 p<0.001 OMA 300 mg Placebo Placebo OMA 75 mg OMA 150 mg OMA 300 mg p<0.001

120. 76% reduction in weekly hives score with Omalizumab 300 mg vs baseline at 12 weeks 1 123 Omalizumab 300 mg Placebo 7 6% Patients were receiving background treatment of non-sedating H1-antihistamines at approved doses; all p-values are relative to the placebo group; adapted from Maurer M, et al . 2013; data represent the modified intention-to-treat( mITT ) population Asteria II 1. Maurer M, et al. N Engl J Med 2013;368:924–35.

121. Xolair ® safety was investigated in over 700 patients in the CSU Phase III clinical program 1 124 Overall incidences of adverse reactions were similar between O malizumab and placebo patients. 2 1. Xolair Basic Prescribing Information 2. Kaplan A, et al. J Allergy Clin Immunol 2013;132:101–9

122. Incidences of adverse reactions between Omalizumab and placebo patients 1 125 Adverse reactions* reported during Weeks 1–12 From the pooled CSU safety database (ASTERIA I, ASTERIA II, GLACIAL) Adverse reactions (%) Placebo† Xolair ® 300 mg† Sinusitis 2.1 4.9 Headache 2.9 6.1 Arthralgia 0.4 2.9 Adverse reactions* reported during Weeks 1–24 From the pooled CSU safety database (ASTERIA I, GLACIAL) Upper respiratory tract infection 3.1 5.7 Injection site reaction** 0.8 2.7 Xolair basic prescribing information *Events occurring in ≥1% of patients in any treatment group and ≥2% more frequently in any Xolair ® treatment group than in the placebo group **Despite not showing a 2% difference to placebo, injection site reactions were included as all cases were assessed as related to study treatment †Patients were receiving background treatment of non-sedating H1-antihistamines at approved doses (ASTERIA I/II) or non-sedating H1-antihistamines (up to 4x the approved dose) plus H2-antihistamines and/or leukotriene-receptor antagonists (GLACIAL)

123. Xolair ® has an established safety profile based on long-term use in severe allergic asthma 126 Safety evaluated in >9,300 subjects receiving O malizumab in clinical programs. 1 Omalizumab has >400,000 patient years’ experience, since US approval in 2003, and EU approval in 2005. 1 In the US, Xolair ® is licensed for adults and adolescents (≥12 years of age) with moderate to severe persistent allergic asthma. 2 In the EU, Xolair ® is licensed for adults and adolescents (≥6 years of age) with severe persistent allergic asthma. 3 Xolair ® is now approved in >90 countries, including the EU. 1 Sixteenth Periodic Safety Update Report (PSUR) dated 15.02.2013. Novartis data on file . Xolair ® US summary of product characteristics 2014. Xolair ® EU summary of product characteristics 2014.

124. Contraindication 127 Hypersensitivity to the active substance or to any of the excipients. Xolair ® Basic Prescribing information