CSU and AngioedemaDr Tshegofatso Mabelane

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• What is CSU

• What has changed in the thinking behind the disease in terms of presentation,

cause , diagnosis

• What’s new in the 2018 international CSU treatment guidelines

• Current treatment – pros and cons

Content

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

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

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

Urticaria can be classified based on duration, frequency, and cause

Chronic spontaneous urticaria

Chronic

Spontaneous

InducibleUrticaria

Known causes (including autoimmune,

infection)

Unknown causes

Chronic spontaneous urticaria (CSU) can be defined as the spontaneous daily, or almost daily, occurrence of itchy hives, angioedema or both, 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

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

Acute

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

CSU is a chronic disease whose duration is estimated to be 1–5 years in most cases1,2

• 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 Immunol2002;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

Epidemiology

• CSU affects up to 1% of the population at any given time, accounting for approximately two-thirds of cases of CU1–3

• Female:male ratio is 2:11

• All age groups can be affected, but peak incidence is between 20–40years of age1

• No apparent relationship between urticaria prevalence and education, income, occupation, place of residence or ethnic background1

• Evidence suggests that the prevalence of CU may be increasing4–8

1. Maurer M, et al. Allergy 2011;66:317−30;2. Kozel MM, et al. Arch Dermatol 1998;134:1575–80;

3. Saini SS. Curr Allergy Asthma Rep 2009;9:286–90;4. Hellgren L. Acta Allergol. 1972;27:236–40;

5. Gaig P, et al. J Investig Allergol Clin Immunol. 2004;14:214–20;6. Zuberbier T, et al. Clin Exp Dermatol. 2010;35:869–73;

7. Zazzali JL, et al. Ann Allergy Asthma Immunol. 2012;108:98–102;8. Furue M, et al. J Dermatol. 2011;38:310–20.

CU = chronic urticariaCSU = chronic spontaneous urticaria.

CSU adversely affects quality of life (QoL)• Many aspects of QoL are found to be reduced in patients with CSU,1 with the presence of

angioedema further impairing QoL scores2

CSU impacts

Daily living

Leisure

Self-perception

Treatment-induced restrictions

Mental status

Social functions

Physical activityChoresEating

ConcentratingSleeping

Restricted choice of clothingLimiting hobbies

Avoiding sun exposure

LonelinessConspicuousness

Anxiety over the futureFeeling unhygienic

Effect on everyday activitiesFinancial burden

Discomfort

TiredStressed

OverwhelmedAnxious

Impact on relationshipsImpact on sexuality

1. Kang MJ, et al. Ann Dermatol 2009;21:226–9;2. Silvares MRC, et al. Rev Assoc Med Bras 2011;57:577−82.

CSU = chronic spontaneous urticaria; QoL = quality of life.

The extent of impaired QoL in patients with CIU/CSU

• Studies indicate that QoL scores in patients with CIU/CSU are similar to or worse than those in many other diseases, even those that are more serious• QoL is worse than in psoriasis, atopic eczema, basal cell carcinoma and

leprosy1

• QoL scores for energy, social isolation and emotional reactions are similar to those in patients waiting for bypass surgery2

• The socioeconomic cost of CSU is high in terms of direct medical costs and indirect costs, such as lost wages because of absences from work 1,2

1. Silvares MRC, et al. Rev Assoc Med Bras 2011;57:577−82;2. O'Donnell BF, et al. Br J Dermatol 1997;136:197–201

The pathogenesis of CSU is yet to be fully characterized1

CSU = chronic spontaneous urticaria. 1. Zuberbier T, et al. Allergy 2009;64:1417–26.

Hives

Reflex erythema

Itch

Key symptoms of CSU

?The pathophysiology underlying CSU

is thought to be mediated by aberrant release of histamine and

other inflammatory mediators from mast cells and basophils

Angioedema

Pathogenesis

CSU skin lesions show recruitment of mast cells and also basophils, neutrophils, eosinophils and T lymphocytes1–6

Hive (wheal)

Mast cell

BasophilCD3+/CD4+/CD8+ T lymphocyte

EosinophilNeutrophil

1. Elias J, et al. J Allergy Clin Immunol 1986;78:914–8; 2. Natbony S, et al. J Allergy Clin Immunol 1983;71:177–83;3. Sabroe RA, et al. J Allergy Clin Immunol 1999;103:484–93; 4. Ying S, et al. J Allergy Clin Immunol 2002;109:694–700;

5. Zuberbier T, et al. Allergy 2009;64:1417–26; 6. Ito Y et al. Allergy 2011;66:1107–13.

EAACI/GA2LEN/EDF/WAO guidelines1 state that urticaria is a mast cell-driven disease

• Activated mast cells release histamine and other mediators

• These mediators activate sensory nerves

• Mast cell activating signals in urticaria are ill-defined and likely to be heterogeneous and diverse

CSU = chronic spontaneous urticaria; EAACI = European Academy of Allergy and Clinical Immunology;

IgE = immunoglobulin E; 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.

As IgE is key to the release of histamine and other pro-inflammatory mediators from mast cells and basophils following degranulation, it may play a role in CSU

Pathogenesis of CSU: the current story• CSU is thought to be either autoimmune or idiopathic1,2

CSU = chronic spontaneous urticaria; IgE = immunoglobulin E;IgG = immunoglobulin G; TPO = thyroperoxidase.

1. Kaplan AP, Greaves M. Clin Exp Allergy 2009;39:777–87;2. Altrichter S, et al. PLoS One 2011;6:e14794;

3. Staubach P, et al. Mycoses 2009;52:334–8;4. Metz M, Maurer M. Curr Opin Allergy Clin Immunol

2012;12:406–11.

55% Idiopathic

CSU

Activation of mast cells(and basophils?)

?

Release of histamine and other inflammatory mediators

Symptoms

Allergic ?

IgG anti-IgE receptor

autoantibodies35–40%

Autoantibodies including

IgE anti-TPO (up to 33%)

IgG anti-IgE autoantibodies

5–10%

Other (unknown) autoantibodies/

serum factors

45% Autoimmune

▪ General consensus: allergy is not an underlying cause of CSU. However, total IgE levels are typically higher in CSU patients than in healthy individuals3,4

Diagnosis

• A routine patient evaluation should comprise a thorough history and physical examination1

• Obtaining a thorough history is the most important diagnostic procedure, and should include questions relating to the following1

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

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

Recommended diagnostic tests for spontaneous urticaria1

*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;

NSAID = nonsteroidal anti-inflammatory drug.

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

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• 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• Lesional skin biopsy

Recommended assessment tools for CSU1

CSU = chronic spontaneous urticaria. 1. Zuberbier T, et al. Allergy 2014;69:868–87.

AngioedemaHives (wheals)

and associated itch

• Urticaria activity score (UAS)

• Chronic urticaria quality of life questionnaire (CU-Q2oL)

▪ Angioedema activity score (AAS)

▪ Angioedema quality of life questionnaire (AE-QoL)

Management

• The aim of therapy for CSU is quick and complete symptom control1

• Symptomatic treatment aims to reduce the effect of mast cell/basophil (effector cell) mediators, e.g. histamine, on target organs leading to the symptoms of urticaria2,3

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

3. Urticaria and angioedema. Zuberbier T, Grattan C, Maurer M editors. Berlin: Springer-Verlag, 2010

EAACI/GA2LEN/EDF/WAO urticaria guidelines: what has changed in the recent update?

1. Adapted from Zuberbier T, et al. Allergy 2009;64:1427‒43;2. Zuberbier T, et al. Allergy 2014;69:868–87, .

Second generation H1-antihistamine

Up-dosing (up to 4 licensed dose)§ of second generation H1-antihistamine

If symptoms persistafter 2 weeks

If symptoms persist after 1–4 further weeks

Add* omalizumab,‡ cyclosporin A§ or montelukast§

Exacerbation: systemic corticosteroid (3–7 days)

2nd line

1st line

3rd line

Updated (2013) guidelines2

Position omalizumab as a

3rd line treatment option

Changes in the 2013 update include:

▪ H2-antihistamine and dapsone are no longer

included

▪ Montelukast is specified as a third-line

therapy

▪ Omalizumab and cyclosporin A are

recommended as third-line therapies

Zuberbier T, et al. Allergy 2017 revision and update

Updated (2017) guidelines2

Position omalizumab as a

3rd line treatment

H1-antihistamines are ineffective in many patients with CSU

1. Maurer M, et al. Allergy 2011;66:317–30; 2. Zuberbier T, et al. Allergy 2009;64:1427–43;3. Asero R. Clin Exp Dermatology; 2007; 32:34-38; 4. Simons FER. N Engl J Med.2004;351:2203–2217;

5. Holgate ST, et al. Clin Exp Allergy 2003;33:1305–1324; 6. Hindmarch I, et al. Curr Med Res Opin 2001;17:241–255; 7. Shamsi Z, Hindmarch I. Hum Psychopharmacol Clin Exp 2000;15(suppl 1):S3–S30;

8. Casale, et al. J Allergy Clin Immunol 2003;111:S835–S842..

▪ Second generation H1-antihistamines fail to control symptoms in up to 50% of CSU patients at licensed doses1

▪ Guidelines recommend an up to 4-fold dose increase of H1-antihistamine in patients with an insufficient response at licensed doses2

▪ It has been suggested that the increase in dose not only blocks histamine mediated effects but also reduces mast cell activation and has an impact on various cytokine and endothelial adhesion molecules3

▪ Updosing of H1-antihistamines improves treatment responses, but up to one third of patients remain symptomatic1,2

▪ Some second generation H1-antihistamines (eg. cetirizine, loratadine) potentially cause sedation when licensed doses are exceeded4–8

Other, unlicensed, treatments are also recommended as add-on therapy for the treatment of refractory CSU1

• Other, unlicensed, treatments are also recommended by guidelines as add-on therapy to second generation H1-antihistamines in refractory CSU1

• The level of evidence for the efficacy of leukotriene receptor antagonists eg. 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.

Omalizumab is a humanized monoclonal IgG antibody against IgE, with low immunogenicity1

• To reduce potential for human anti-mouse antibody (HAMA) response, ‘humanization’ of the murine anti-IgE was performed

• Portions of the murine CDRs were grafted onto a human IgG1 kappa framework

• Omalizumab consists of 95% IgG1 kappa human framework and 5% mouse sequence, which is hidden from the immune system when omalizumab binds to IgE

CDR = complementarity-determining region.

1. Boushey H Jr. J Allergy Clin Immunol 2001;108:S77–83;2. Adapted with permission from Boushey H Jr. J Allergy Clin Immunol

2001;108:S77–83.

Murine CDRs(5% of molecule)

IgG1 kappa human

framework(95% of molecule)

Structure of omalizumab2

Mechanism of Action: Omalizumab inhibits binding of IgE to Fc RI on the surface of mast cells and basophils1-3

• Binding of serum IgE by omalizumab decreases expression of the high affinity receptor; leading to decreased mast cell degranulation

• Clinical response to omalizumab in CIU/CSU is faster than in SAA, immediate effects can be seen within a few days to one week following the first dose

Indications for Omalizumab?

• Omalizumab is indicated as add-on therapy for the treatment of chronic spontaneous urticaria in adult and adolescent (12 years and above) patients with inadequate response to H1-antihistamine treatment1

Omalizumab dosing schedule

• Omalizumab is administered by subcutaneous injection and is supplied either as a pre-filled syringe or lyophilised formulation for reconstitution1

• The approved dose in is 300 mg (2 x 150 mg) every 4 weeks1

• Patients should be observed following administration of omalizumab1

• Prescribers should periodically reassess the need for continued therapy; clinical trial experience of treatment beyond 6 months in this indication is limited

What are other causes of angioedema?

• Hereditary Angioedema

• Food allergy

• Medication

• Unknown cause of angioedema

Patient 1

• 23yr old presented to clinic with severe tummy-ache and vomiting after having a flu and fever few days back.

• She further developed swelling of her face WITHOUT hives.

• Her aunt reported a family history of her mother suffering from severe swellings and sometimes difficulty in breathing.

• She was given adrenalin and antihistamine but got worse.

• She was transferred to the hospital, where she received blood products that contained proteins and her symptoms resolved.

• Her doctor gave her a card with details of what to do if she gets an attack.

• The clinic and ambulance was notified of her condition and the doctor organised for her local clinic to have the blood product for her in case of an acute attack.

Hereditary angioedema

• Rare genetic disorder, however 25% spontaneous genetic mutation.

• Commonly affects the arms, legs, face, abdomen

• Symptoms usually show up in childhood and get worse during the teen years.

• Triggers: infection, dental work, minor trauma, meds (NSAIDs/ACE I)

• C1 esterase inhibitor dysfunction

• C4 and C1 esterase inh testing for diagnosis

Patient 2

• 9month old with history of swelling of mouth and hives within 30minutes of eating a small piece of peanut butter bread for the first time.

• He was given allergex syrup and the symptoms resolved within 1 hour.

• His mother consulted the doctor at the hospital, who advised for him to avoid the food, gave him allergex only because it was not a severe reaction and referred to an allergy specialist.

❑Food Allergy

Patient 3

• 38yr old lady diagnosed with hypertension and started on pharmapress.

• She developed one sided swelling of lip and tongue after using medication daily for 2years.

• She consulted the doctor at the clinic, who changed her medication to HCTZ, advised her to avoid it in future and gave her a medic alert.

• Her symptoms resolved after 3months.

Angioedema due to drug allergy

• Common medication causing swelling are antihypertensive e.g. Enalapril , NSAIDs

• Swelling can start many years (>20yrs) on drugs and take up to 3months to resolve after stopping.

• No reliable tests for diagnosis

QUESTIONS