chronic urticaria

Updates in Chronic Urticaria Management

BY

PROF. ASHRAF OKBA

HEAD OF THE DEPARTMENT OF

IMMUNOLOGY AND ALLERGY

AIN SHAMS UNIVERSITY

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 urticaria treatment

Urticaria is a disease characterized by thedevelopment of wheals (hives), angioedema, or both.

Urticaria Definition:

Acute urticaria is defined as the occurrence of spontaneouswheals, angioedema, or both for <6 weeks, while in chronicurticaria 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

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



Angioedema Definition

• /an·gio·ede·ma/ a vascular reaction involving the deep dermis or subcut

aneous 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.



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

Acute Urticaria: ˂ 6 Weeks

Chronic Urticaria: ≥ 6 Weeks

Classification of Urticarias



Classification of Urticarias1

1. Adapted from: Zuberbier T, et al. Allergy 2014;69 (7):868–87.

Chronic spontaneous

urticaria

Chronic

Acute

Spontaneous

InducibleUrticaria

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

New2013

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)

For CSU, the cause of the spontaneous urticariasapproaches zero because the etiology is not known even though there is an association with autoimmunity in approximately 45% of patients and,

The 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)

Chronic urticariaNow 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 known1

or unknown causes

The term “ Chronic Idiopathic Urticaria”

should be avoided

Physical urticarias• Symptomatic dermographism2

• Cold urticaria3

• Delayed pressure urticaria4

• Solar urticaria

• Heat urticaria5

• 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

*Guidelines:

EAACI, European Academy of Allergology and Clinical Immunology

GA2LEN, Global Allergy and Asthma European Network

EDF, European Dermatology Forum

WAO, World Allergy Organization

1. Zuberbier T, et al. Allergy 2009;64:1417–26;

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

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.

Prevalence of Urticaria With and Without Angioedema

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%

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

1616

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

In most cases, the duration of CSU is estimated to be 1–5 years1

However, for some patients the disease can last longer, sometimes more than 25 years1

Year 25

Years since diagnosis

Another 20% will resolve

(with or without treatment)

within 5 years of onset2

50% will resolve (with or

without treatment) within

6 months of onset2

Another 20% will resolve


within 3 years of onset2

Another <2% will resolve


within 25 years2

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

18CINDU: 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

MC

Release of

Mediators

including

Histamine

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 PathogenesisSymptoms are brought about by the degranulation of skin mast cells

IgE FceRI

1. Altrichter S, et al. PLoS One 2011;6:e14794;

2. Hide M, et al. N Engl J Med 1993;328:1599−604

Mast cells in some patients are activated by autoallergic or autoimmune mechanisms1

• histamine-releasing immunoglobulin G (IgG) autoantibodies against the high-affinity immunoglogulin E (IgE) receptor (FcεRI) or IgE itself are present in the circulation,2 and IgE autoantibodies may also be present1

Auto-allergy

allergen

1.Autoantigen/autoallergen

3. endogenous anti-IgE

antibody

Auto-immunity

2. anti-FcεRI

1.IgE against self

Allergy

MC

IgE

FcεRI

Pathophysiology of urticariaMast cell stimulation

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.

• Recently 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

Complement Ca5

Thrombin

FcἐRI

IgG autoantibodies

Auto-antigen:TPO

IgE autoantibodies

mR

NA

Free IgE

Pathophysiology of urticaria (Cont.) Mast cell stimulation

The slide is for illustrative purpose

23

Complement Ca5

Thrombin

FcἐRI

Free IgE

IgG autoantibodies

Auto-antigen:TPO

IgE autoantibodies

mR

NA

Pathophysiology of urticaria (Cont.) Mast cell stimulation (Immune-mediated urticaria )

The slide is for illustrative purpose

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

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:

25Zuberbier T, Aberer W, Asero R, et al. The EAACI/GA²LEN/EDF/WAO guideline for the definition, classification, diagnosis and


2626

1. Time of onset of disease

2. Frequency and duration of wheals

3. Diurnal variation

4. Occurrence in relation to weekends,

holidays, and foreign travel

5. Shape, size, and distribution of

wheals

6. Associated angioedema

7. Associated subjective symptoms of

lesion, e.g. itch, pain

8. Family and personal history

regarding urticaria, atopy

9. Previous or current allergies,

infections, internal diseases, or other

possible causes

10. 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 historyQuestions should be asked regarding the following items:



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 historyQuestions should be asked regarding the following items:

2828

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.



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 subtypes1

3030

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

3131

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.

3232

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

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 patients1

• patients with autoimmune CSU appear to have more severe disease2

- more severe clinical features have been reported, including more wheals, larger wheal size, higher itch scores3– 5

- longer duration of disease5–7

- higher requirement for antihistamine medication7

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

• Should routine diagnostic measures be performed in acute urticaria?

• We recommend against any routine diagnostic measures in acute urticaria (strong recommendation/clinical consensus).



• 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).



Diagnostic algorithm for patients presenting with wheals,

angioedema, orboth

36

37

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

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 FcεRI) 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

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

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

•

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.

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

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

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

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

•

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 IgEreceptor 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.

•

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)

49

Urticaria Burden

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:

1. The unpredictability of the attacks.

2. Lack of quality sleep (due to pruritus).

3. Fatigue caused by treatment.

4. Side-effects.

5. Cosmetic disfigurement.

Quality of life

Allergy 2011; 66: 317–330.50

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 scores2

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

1. Kang MJ, et al. Ann Dermatol 2009;21:226–9;

2. Silvares MRC, et al. Rev Assoc Med Bras 2011;57:577−82

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

5454

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

Socioeconomic 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

0

50

100

150

200

250

300

Direct costs/patient/year ($US)

Laboratory

Outpatient visits

ED/hospital visits

Medication

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

0

50

100

150

200

250

300

Indirect costs/patient/year in lost wages ($US)

Travel tooutpatient visit

Absence fromwork

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

$U

S

$U

S

How to assess disease activity and quality of life?

56

Disease activity

Quality of life

UAS AAS

CU-Q2ol AE-Qol

Wheal Angioedema

5757

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

0 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



Treatment of Urticaria

63

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

6464

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

1. Elimination/avoidance of the cause or trigger/stimulus

2. Symptomatic pharmacological treatment by reducing mast cell mediator release and/or the effect of these mediators at the target organ

3. 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


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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


Trigger

CauseMast cell-

activating

signal

Mast cell

activation

Mast cell

mediators

Urticaria

reaction

causal symptomatic

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.



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)



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Trigger

CauseMast 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


causal

Guidelines Recommendations 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

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Continuous treatment with H1-antihistamines is central to the management of CU

Many symptoms of urticaria are mediated primarily by histamine

• Histamine H1 receptors are located on endothelial cells and sensory nerves

• H1-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 H1-antihistamines

Use of first-generation (sedating) antihistamines is not recommended for routine management of urticaria

Modern second-generation H1-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.



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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?

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 H1-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;



Treatment of antihistamine-refractory patients:

Ciclosporin A

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

Description of LTRAs has been changed since 2009 and now notes that the best evidence is for montelukast.

LTRA = leukotriene receptor antagonist.



Treatment of antihistamine-refractory patients:

LTRAs and corticosteroids

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.

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Treatment of antihistamine-refractory patients:Omalizumab



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 TNFα 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-TNFα 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; TNFα = tumour necrosis factor alpha; UV = ultraviolet.



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

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Thank You

Diagnostic Approach