U023 - Urticaria Management07/28/2018, 7:30 AM

Columbus KL

Prof. Dr. Kiran GodseMD,PhD,FRCP(Glasgow)

Professor of dermatologyD.Y.Patil University School of Medicine

Nerul, Navi Mumbai,India

Conflict of interest: None

Urticaria is a dermatological disorder characterized by the sudden appearance of itchy hives (wheals), angioedema or both1

A hive consists of three typical features:

1. Central swelling of variable size, usually surrounded by a reflex erythema

2. Associated itching (pruritus), or sometimes a burningsensation

3. Usually resolves within a few hours and always by 24 hours

1. Zuberbier T, et al. Allergy 2014;69:868–87

Hives: Superficial swellings with pale centressurrounded by a red flare

Angioedema is typically characterized by:

1. Sudden, pronounced swelling of the lower dermis and subcutis

2. Sometimes pain rather than itching

3. Frequent involvement below mucous membranes

4. Up to 72 hours for resolution

Angioedema of the lips: Pronounced swelling of soft tissue in the mouth

The terms ‘itch/pruritus’, and ‘hive/wheal’ are interchangeable. For the purpose of this training tool, itch and hive will be used to describe these key symptoms of urticaria

Chronic urticaria (CU)

Chronic spontaneous urticaria (CSU) Chronic inducible urticaria (CINDU)

Physical Other

EAACI/GA2LEN/EDF/WAO guidelines: definition and classification urticaria1,2

EAACI = European Academy of Allergy and Clinical Immunology;GA2LEN = Global Allergy and Asthma European Network;EDF = European Dermatology Forum;WAO = World Allergy Organization.

1. Zuberbier T, et al. Allergy 2014;69:868–87; 2. Zuberbier T, et al. Allergy 2009:64:1417–26.

• Spontaneous development of symptoms (no external specific trigger)

• Includes patients with known (autoimmune, infection, etc.) and unknown causes for urticaria

• Symptoms induced by a specific trigger

• Cold

• Delayed pressure

• Heat

• Solar

• Dermographic

• Vibratory

• Aquagenic

• Cholinergic

• Contact

Urticaria is characterized by the sudden appearance of hives (wheals), angioedema or both lasting for ≥6 weeks

CSU is a chronic disease whose duration is estimated to be 1–5 years 1,2

• In very rare cases, CSU can persist for up to 50 years1

CSU = chronic spontaneous urticaria. 1. Maurer M, et al. Allergy 2011;66:317–30;

2. Adapted from: Beltrani VS. Clin Rev Allergy Immunol 2002;23:147–69.

Of the diagnosed CSU patient population:

Years since diagnosis

50% will resolve within 6 months

of onset2

20% will resolve within 3 years2

20% will resolve within 5–10 years2

<2% will resolve within 25 years2

Year 1 Year 2 Year 4Year 3 Year 5 Year 25

Recent revisions to the EAACI/GA2LEN/EDF/WAO guidelines have updated the CSU diagnosis steps1

1. Take a thorough history Patients should be questioned regarding:Time-of-onset of diseaseFrequency/duration of and provoking factors* for hives and/or angioedema

2. Physical examination of the patient

– This should include a diagnostic provocation test including drug, food and physical tests only where it is indicated by history

*eg. stomach or bowel problems;CSU = chronic spontaneous urticaria;EAACI = European Academy of Allergy and Clinical Immunology;GA2LEN = Global Allergy and Asthma European Network;EDF = European Dermatology Forum;WAO = World Allergy Organization. 1. Zuberbier T, et al. Allergy 2014;69:868–87

Histo

ryD

iagno

stic testsTreatm

ent

ACE inhibitor treatment?

+ +--

+ - + - - + - +

+ - - +

- +

Signs of vasculitis in biopsy?

Are symptoms inducible?

Provocation test

Acquired/ hereditary AID

Urticarial vasculitisChronic

spontaneous urticaria

Chronic inducible urticaria

HAE I–IIIAAE

ACE-inhibitor induced AE

Interleukin-1 Histamine and other Mast Cell Mediators Bradykinin

and/or

Auto-inflammatory disease?

Average hive duration >24 hours?

HAE or AAE? Remission after stop?

Hives Angioedema

Recurrent unexplained fever?Joint/bone pain? Malaise?

Histo

ryD

iagno

stic testsTreatm

ent

Recurrent unexplained fever?Joint/bone pain? Malaise?

ACE inhibitor treatment?

+ +--

+ - + - - + - +

+ - - +

- +

Signs of vasculitis in biopsy?

Are symptoms inducible?

Provocation test

Acquired/ hereditary AID

Urticarial vasculitisChronic

spontaneous urticaria

Chronic inducible urticaria

HAE I–IIIAAE

ACE-inhibitor induced AE

Interleukin-1 Histamine and other Mast Cell Mediators Bradykinin

and/or

Auto-inflammatory disease?

Average hive duration >24 hours?

HAE or AAE? Remission after stop?

Hives Angioedema

EAACI/GA2LEN/EDF/WAO urticaria guidelines: paths to diagnosis of CSU1

AAE = acquired angioedema due to C1-inhibitor deficiency; ACE = angiotensin converting enzyme AE = angioedema; AH = antihistamine; AID = auto-inflammatory disease; HAE = hereditary angioedema. EAACI = European Academy of Allergy and Clinical Immunology; GA2LEN = Global Allergy and Asthma European Network; EDF = European Dermatology Forum; WAO = World Allergy Organization.

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

Chronic spontaneous urticaria diagnostic workup

• Exclude differential diagnoses

• Rule out severe inflammation

• Measure disease activity and impact

Rule out severe inflammatory process

• CRP/ ESR

• COMPLETE BLOOD COUNT

Management plan

• Removal of any identified cause

• Avoidance of aggravating factors

• Advice and information

• Lotions for symptomatic relief

• First line drugs (Non sedating Antihistamines)

• Second line interventions as per clinical situation

• Third line immunosuppressive therapies

Basic treatment: Avoidance of triggers and relevant physical factors if physical urticaria/angioedema is present

THE EAACI/WAO Guideline The AAAAI/ACAAI Guideline

STEP 1 Monotherapy with sgAH Monotherapy with sgAH

if adequate control: After 2-4 weeks or earlier, if symptoms are intolerable

One or more of the following:-Dose advancement of sgAH used in step 1-Add another sgAH-Add H2 antagonist-Add LTRA-Add fgAH, to be taken at bed time

assess for patient’s tolerance and efficacy

STEP 2 Increase sgAH dose (upto4x)

if adequate control: After 2-4 weeks or earlier, if symptoms are intolerable

assess for patient’s tolerance and efficacy

STEP 4 Add on sgAH : CyclosporineAdd an alternative agent:-Omalizumab or cyclosporine-other anti-inflammatory agents, immunosuppressants or biologics

STEP 3 Add on to sgAH : Omalizumab

Dose advancement of potent antihistamine (e.g. Hydroxyzine or doxepin) as tolerated

If adequate control: within 6 months or earlier, if symptoms are intolerable assess for patient’s tolerance and efficacy

TWO SUBGROUPS OF RESPONDERS to Omalizumab

The heat map of individual patient-level UAS7 and ISS data confirmed two subgroups of responders to omalizumab in CSU:

• Subgroup one: early treatment responders – patients who responded after one dose of omalizumab (<4 weeks)

• Subgroup two: late treatment responders – patients who need additional time to respond (up to 24 weeks)

Increased IgE levels linked to faster relapse in omalizumab discontinued CU patients

1. Kaplan A, et al. J Allergy Clin Immunol. 2016;137(2):474-81Confidential. Data on file.

Table X

• Dapsone• Methotrexate• Autoserum therapy• Azathiopurine• Tranexamic acid• Colchicine• H2 antihistamines• Montelukast• Phototherapy• Sulfasalazine• IVIg

Only trials of low quality or case series have been published

Recommended treatment for CSU (1)

• Second generation H1-antihistamines are recommended first-line treatment for CSU1,2

– However, standard therapy with licensed doses of H1-antihistamines is often ineffective; up to 50% of patients have an inadequate response to approved doses of H1-antihistamines1

• Guidelines recommend an up to 4-fold dose increase* in H1-antihistamine second-line, in patients with an inadequate response to H1-antihistamines at licensed doses2

– This results in a higher degree of efficacy in some, but not all, patients, with up to one third of patients remaining unresponsive1–4

*Not licensed.

1. Maurer M, et al. Allergy 2011;66:317‒30; 2. Zuberbier T, et al. Allergy 2014;69:868–87

3. Staevska M, et al. J Allergy Clin Immunol 2010; 125(3):676-82; 4. Sanchez-Borges M, et al. World Allergy Organ J 2012; 5(11):125-47

Recommended treatment for CSU (2)

• Treatment options for patients refractory to second generation H1-antihistamines, even at higher doses, are limited

• Guidelines recommend third-line addition of omalizumab, cyclosporin A to existing H1-antihistamine treatment1

– Omalizumab 300 mg is approved in the EU/the US for the treatment of CSU/CIU in adult and adolescent (12 years and above) patients with inadequate response to H1-antihistamine treatment/who remain symptomatic despite H1-antihistamine treatment2,3

– The level of evidence for the efficacy of montelukast in urticaria is low1

– Efficacy of ciclosporin A in combination with a second-generation H1-antihistamine has been demonstrated in clinical trials, but it is associated with a high incidence of adverse effects1

1. Zuberbier T, et al. Allergy 2014;69:868–87;2. Xolair® SmPC 2014;

3. Xolair® PI 2014.

THANK YOU EMAIL DRGODSE@HOTMAIL.COM