Chronic Spontaneous Urticaria

1. Overview

Chronic Urticaria (CU) is defined as the recurrent occurrence of wheals (hives), angioedema, or both for more than 6 weeks. It affects 0.5-1% of the population and has a profound impact on quality of life comparable to ischemic heart disease. [1,2]

Unlike acute urticaria, which is often triggered by external allergens, chronic urticaria is predominantly an autoimmune-mediated condition with spontaneous mast cell and basophil activation. The identification of autoimmune mechanisms and the advent of targeted biologic therapies have revolutionized management. [3]

Key Classification (EAACI 2022)

Chronic urticaria is divided into two major subtypes: [4]

1. Chronic Spontaneous Urticaria (CSU):

   • No identifiable external trigger
   • 60-70% of all chronic urticaria cases
   • Autoimmune pathogenesis in 40-50% (Type I autoimmunity) and 30-40% (Type IIb autoimmunity)
   • Spontaneous mast cell degranulation

2. Chronic Inducible Urticaria (CIndU):

   • Reproducible physical or environmental trigger
   • 20-30% of cases (often coexists with CSU)
   • Subtypes include:
     • Symptomatic dermographism (stroking/friction)
     • Cold urticaria (cold exposure)
     • Delayed pressure urticaria (sustained pressure)
     • Solar urticaria (UV/visible light)
     • Heat urticaria (localized heat)
     • Vibratory angioedema (vibration)
     • Cholinergic urticaria (elevated core temperature, exercise, sweating)
     • Contact urticaria (direct skin contact with allergen)
     • Aquagenic urticaria (water contact - very rare)

Clinical Features of a Wheal

The wheal is the pathognomonic lesion of urticaria: [1]

• Central swelling (raised edema) of variable size
• Surrounding erythema (flare reaction)
• Intense itching (pruritus) - key distinguishing feature
• Transient nature: Individual lesions resolve within 24 hours without leaving bruising or scarring
• Migratory pattern: Lesions appear and disappear at different sites

Key Distinction: Wheals that persist > 24 hours or leave bruising suggest urticarial vasculitis, not CSU.

Epidemiology

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2. Pathophysiology

Mast Cell and Basophil Activation - The Central Event

The hallmark of CSU is spontaneous activation of skin mast cells and circulating basophils, leading to degranulation and release of inflammatory mediators. [3,9]

Mediators Released:

• Histamine: Vasodilation, vascular permeability, pruritus
• Leukotrienes (LTC4, LTD4, LTE4): Prolonged vascular permeability
• Prostaglandin D2: Vasodilation and erythema
• Platelet-activating factor (PAF): Inflammation
• Tryptase: Marker of mast cell activation
• Cytokines (IL-4, IL-5, IL-13, TNF-α): Sustained inflammation

┌─────────────────────────────────────────────────────────────────────────────┐
│                    CHRONIC URTICARIA PATHOPHYSIOLOGY                        │
├─────────────────────────────────────────────────────────────────────────────┤
│                                                                             │
│   ┌─────────────────────────────────────────────────────────────────────┐   │
│   │                 MAST CELL & BASOPHIL ACTIVATION                     │   │
│   │  • Spontaneous degranulation in skin and systemically               │   │
│   │  • Release: Histamine, Leukotrienes, Prostaglandins, PAF, Tryptase │   │
│   │  • Basophil Histamine Release Assay (BHRA) positive in 50-60%      │   │
│   └─────────────────────────────────────────────────────────────────────┘   │
│                                    ↓                                        │
│               ┌────────────────────┴─────────────────────┐                  │
│               ↓                                          ↓                  │
│   ┌───────────────────────────┐          ┌──────────────────────────┐       │
│   │ TYPE I AUTOIMMUNITY       │          │ TYPE IIb AUTOIMMUNITY    │       │
│   │ ("Auto-allergic")         │          │ (Autoantibody-mediated)  │       │
│   │                           │          │                          │       │
│   │ • IgE against self-       │          │ • IgG anti-FcεRI         │       │
│   │   antigens (e.g., TPO,    │          │ • IgG anti-IgE           │       │
│   │   dsDNA, thyroglobulin)   │          │ • Cross-link receptors   │       │
│   │ • Cross-link FcεRI on     │          │ • ASST positive (40-50%) │       │
│   │   mast cells/basophils    │          │ • BAT positive           │       │
│   │ • 40-50% of CSU cases     │          │ • 30-40% of CSU cases    │       │
│   └───────────────────────────┘          └──────────────────────────┘       │
│                                    ↓                                        │
│   ┌─────────────────────────────────────────────────────────────────────┐   │
│   │              ADDITIONAL PATHOGENIC MECHANISMS                       │   │
│   │  • Coagulation cascade activation (thrombin, Factor Xa)             │   │
│   │  • Complement activation (C5a - mast cell activation)               │   │
│   │  • Eosinophil infiltration and activation                           │   │
│   │  • Reduced regulatory T-cell function (immune dysregulation)        │   │
│   └─────────────────────────────────────────────────────────────────────┘   │
│                                    ↓                                        │
│   ┌─────────────────────────────────────────────────────────────────────┐   │
│   │                    CLINICAL MANIFESTATIONS                          │   │
│   │  • Histamine → H1 receptors → Pruritus (sensory nerve stimulation)  │   │
│   │  • Histamine → Vasodilation → Erythema (flare)                      │   │
│   │  • Histamine → Vascular permeability → Wheal (dermal edema)         │   │
│   │  • Bradykinin/deeper mediators → Angioedema (subcutaneous swelling) │   │
│   └─────────────────────────────────────────────────────────────────────┘   │
│                                                                             │
└─────────────────────────────────────────────────────────────────────────────┘

Autoimmune Mechanisms in CSU

Type I Autoimmunity (IgE-mediated autoallergy)

• Mechanism: IgE antibodies directed against self-antigens (e.g., thyroid peroxidase [TPO], thyroglobulin, double-stranded DNA)
• Effect: These IgE autoantibodies bind to FcεRI on mast cells and basophils; cross-linking by autoantigen triggers degranulation
• Prevalence: 40-50% of CSU patients [10]
• Evidence: Elevated total IgE, positive skin tests to autoantigens

Type IIb Autoimmunity (IgG-mediated)

• Mechanism: IgG autoantibodies against:
  • High-affinity IgE receptor (FcεRI α-subunit) - most common
  • IgE molecule itself (anti-IgE antibodies)
• Effect: IgG autoantibodies cross-link FcεRI receptors → direct mast cell/basophil activation
• Prevalence: 30-40% of CSU patients (termed "autoimmune urticaria") [11]
• Diagnostic tests:
  • "Autologous Serum Skin Test (ASST): Positive in 40-50%"
  • "Basophil Activation Test (BAT): Detects functional autoantibodies"
  • "Western blot/ELISA: Detects anti-FcεRI IgG antibodies"

Coagulation Cascade Involvement

Emerging evidence shows activation of the coagulation system in CSU: [12]

• Elevated D-dimer, prothrombin fragment F1+2, thrombin-antithrombin complexes
• Thrombin and Factor Xa can directly activate mast cells via protease-activated receptors (PAR-1, PAR-2)
• Contributes to inflammation and potentially therapeutic target

Autoimmune Associations

CSU is strongly associated with other autoimmune diseases: [13]

Clinical Pearl: Screening for thyroid autoimmunity (TSH, anti-TPO antibodies) is recommended in all CSU patients, even if euthyroid. Treatment of thyroid disease does not cure CSU, but identifies comorbidity. [4,13]

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3. Clinical Features

History Taking

A systematic approach to history in suspected chronic urticaria:

Duration and Pattern

• How long have wheals been occurring? (Must be > 6 weeks for "chronic")
• Frequency: Daily, several times per week?
• Timing: Worse at night (common), morning, specific times?
• Individual lesion duration: less than 24 hours? (If > 24h → suspect urticarial vasculitis)

Morphology of Lesions

• Size: Small (less than 1cm) vs. large (> 5cm, "giant urticaria")
• Color: Erythematous (red) vs. pale central wheal
• Distribution: Localized or generalized?
• Associated angioedema? (Lips, eyelids, hands, genitals - present in ~40% CSU)

Trigger Assessment - The "6 Ss" for Inducible Urticaria

1. Scratching (Dermographism - most common)
2. Sweating (Cholinergic urticaria - exercise, hot shower)
3. Sun (Solar urticaria)
4. Shivering (Cold urticaria - swimming, cold air)
5. Stress/Sustained pressure (Delayed pressure urticaria - belts, tight shoes)
6. Shower/Water (Aquagenic urticaria - very rare)

Key Question: "Can you make the hives happen on purpose?"

• If YES → likely CIndU
• If NO → likely CSU

Excluding Urticarial Vasculitis

Ask specifically:

• Do individual lesions last > 24 hours?
• Is it painful or burning rather than itchy?
• Do lesions leave a bruise or dark mark when they fade?
• Any joint pains, fever, malaise?

If YES to above: Consider urticarial vasculitis (requires skin biopsy).

Medication and Exposure History

• NSAIDs (aspirin, ibuprofen): Act as "pseudo-allergens"
• worsen existing CSU in 20-30% [14]
• Codeine, opioids: Direct mast cell degranulation
• ACE inhibitors: Cause isolated angioedema (bradykinin-mediated, NOT urticaria)
• Antibiotics (especially β-lactams): Common in acute urticaria, rare in CSU
• Recent infections: Viral infections can trigger CSU onset
• Dietary additives: Preservatives (benzoates), azo dyes (tartrazine) - controversial role

Associated Symptoms

• Pruritus severity: Use 0-10 scale (part of UAS7 scoring)
• Sleep disturbance?
• Impact on daily activities, work, relationships?
• Systemic symptoms: Fever, weight loss, arthralgia (red flags for systemic disease)

Past Medical History

• Autoimmune diseases (thyroid, SLE, RA)?
• Atopic conditions (asthma, eczema, allergic rhinitis) - less common in CSU than acute urticaria
• Previous episodes of urticaria or angioedema?

Family History

• Chronic urticaria (rare familial clustering)
• Autoimmune diseases
• Hereditary angioedema (if isolated angioedema without wheals)

Physical Examination

Skin Examination

• Wheals:
  • "Morphology: Central raised edema with surrounding erythema"
  • Size and distribution
  • "Draw a circle" around a lesion → check 1 hour later (should have moved or disappeared)
• Dermographism test:
  • Stroke skin firmly with tongue depressor or blunt object
  • Positive if linear wheal develops within 5-10 minutes
  • Present in 30-50% of CSU patients
• Excoriations: Evidence of scratching (severe pruritus)
• No residual changes: Absence of purpura, scarring, hyperpigmentation (if present → vasculitis)

Angioedema Assessment

• Sites: Lips, periorbital, hands, feet, genitals
• Character: Non-pitting, non-erythematous swelling
• Mucous membranes: Check oral cavity, tongue (airway risk)
• Airway assessment: Stridor, voice change, difficulty swallowing (EMERGENCY)

Systemic Examination

• Thyroid: Palpate for goiter (autoimmune thyroid disease)
• Lymph nodes: Lymphadenopathy (suggests systemic disease, not CSU)
• Joints: Synovitis (suggests connective tissue disease or urticarial vasculitis)
• Abdomen: Hepatosplenomegaly (systemic disease, mastocytosis)

Provocation Tests (if CIndU suspected)

• Ice cube test: Apply ice cube to forearm for 5 minutes → observe for wheal (cold urticaria)
• Exercise challenge: Treadmill/cycling to induce sweating (cholinergic urticaria)
• Pressure test: Apply 5-7 kg weight to shoulder for 20 minutes → check 6 hours later (delayed pressure urticaria)
• UV exposure: Controlled wavelength exposure (solar urticaria - specialist setting)

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4. Diagnosis and Investigations

Diagnosis

CSU is a clinical diagnosis based on:

1. Recurrent wheals, angioedema, or both for > 6 weeks
2. Individual lesions resolve within 24 hours without residual changes
3. No identifiable external trigger (distinguishes from CIndU)

Urticaria Activity Score (UAS7)

The UAS7 is the validated gold-standard tool for assessing CSU severity: [15]

Daily scoring (for 7 consecutive days):

Weekly UAS7 score: Sum of daily scores (range 0-42)

Interpretation:

• 0: Complete remission
• 1-6: Well-controlled
• 7-15: Mild
• 16-27: Moderate
• 28-42: Severe

Clinical Use:

• Baseline assessment before treatment
• Monitor treatment response (aim for UAS7 ≤6)
• Required for biologic therapy (omalizumab) approval in many healthcare systems

Baseline Investigations (EAACI 2022 Guidelines) [4]

Routine limited workup (recommended for ALL CSU patients):

Extended baseline (consider based on clinical suspicion):

• Thyroid function (TSH) and anti-TPO antibodies: High prevalence of autoimmune thyroid disease (15-30%)
• Total IgE: Often elevated in Type I autoimmunity CSU (non-specific)
• Tryptase: If mastocytosis suspected (usually normal in CSU; elevated in systemic mastocytosis)
• Complement (C3, C4): If urticarial vasculitis or hereditary angioedema suspected
• Hepatitis B/C serology, HIV: In selected patients with risk factors or geographic prevalence
• Stool for ova, cysts, parasites: In endemic areas (Helicobacter pylori eradication has conflicting evidence) [16]

Specialist Investigations (Not Routine)

Autologous Serum Skin Test (ASST) [11]

• Purpose: Detects functional histamine-releasing autoantibodies (IgG anti-FcεRI or anti-IgE)
• Method:
  1. Draw patient's blood, allow to clot, separate serum
  2. Inject 0.05mL autologous serum intradermally
  3. Positive control: histamine; negative control: saline
  4. Read at 30 minutes
• Positive result: Wheal ≥1.5mm larger than negative control
• Interpretation:
  • Positive in 40-50% of CSU patients (suggests Type IIb autoimmune mechanism)
  • Does NOT change management in most cases (omalizumab effective regardless)
  • May predict longer disease duration and severity
• Limitations: False positives (30% healthy controls), not standardized

Basophil Activation Test (BAT)

• Purpose: Functional assay for autoantibodies causing basophil histamine release
• Method: Flow cytometry-based; measures CD63/CD203c upregulation on basophils exposed to patient serum
• Advantages: More specific than ASST, no injection required
• Limitations: Specialized test, expensive, limited availability

Skin Biopsy [17]

• Indication: Suspected urticarial vasculitis (painful lesions > 24h, purpura, systemic symptoms)
• Histology in CSU:
  • Perivascular lymphocytic infiltrate
  • Dermal edema
  • Eosinophils may be present
  • No leukocytoclastic vasculitis (intact vessel walls)
• Histology in urticarial vasculitis:
  • Leukocytoclastic vasculitis (fibrinoid necrosis, neutrophil infiltration, nuclear dust)
  • "Direct immunofluorescence: complement/immunoglobulin deposition"

Challenge Tests (for CIndU diagnosis)

• Ice cube test: Cold urticaria
• Warm water immersion: Heat urticaria
• Exercise/hot bath: Cholinergic urticaria
• Pressure application: Delayed pressure urticaria
• UV irradiation: Solar urticaria (phototesting - dermatology)
• FricTest or dermographometer: Symptomatic dermographism

Investigations NOT Routinely Recommended [4]

The following have LOW yield in CSU and should be AVOIDED unless specific clinical suspicion:

• ❌ Extensive allergy testing (skin prick tests, specific IgE panels): CSU is rarely IgE-mediated to external allergens
• ❌ Food elimination diets: Not evidence-based (exception: very rare cases with pseudo-allergen sensitivity)
• ❌ Exclusion of food additives/preservatives: Conflicting evidence; consider only in refractory cases
• ❌ Imaging (chest X-ray, abdominal ultrasound): Not indicated without specific clinical features
• ❌ Extensive autoimmune panels: Unless clinical features suggest specific systemic disease

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5. Management

Treatment Algorithm (EAACI 2022 Guidelines) [4,18]

The stepwise approach to CSU management is evidence-based and internationally standardized:

┌─────────────────────────────────────────────────────────────────────────────┐
│                    CHRONIC URTICARIA MANAGEMENT (EAACI 2022)                │
├─────────────────────────────────────────────────────────────────────────────┤
│                                                                             │
│   DIAGNOSIS CONFIRMED: CSU (Wheals > 6 weeks, Vasculitis excluded)          │
│                          ↓                                                  │
│   ┌─────────────────────────────────────────────────────────────────────┐   │
│   │                 STEP 1: STANDARD-DOSE sgAH                          │   │
│   │  • Second-generation antihistamine (sgAH) - daily dosing            │   │
│   │  • Options (all equally effective):                                 │   │
│   │    - Cetirizine 10mg OD                                             │   │
│   │    - Fexofenadine 120-180mg OD                                      │   │
│   │    - Bilastine 20mg OD                                              │   │
│   │    - Loratadine 10mg OD                                             │   │
│   │    - Desloratadine 5mg OD                                           │   │
│   │    - Levocetirizine 5mg OD                                          │   │
│   │  • Assess response: 2-4 weeks                                       │   │
│   │  • Target: UAS7 ≤6 (well-controlled)                                │   │
│   └─────────────────────────────────────────────────────────────────────┘   │
│                          ↓ Inadequate control (UAS7 > 6)                     │
│   ┌─────────────────────────────────────────────────────────────────────┐   │
│   │                 STEP 2: UP-DOSED sgAH (2-4x)                        │   │
│   │  • INCREASE same antihistamine up to 4-FOLD standard dose           │   │
│   │  • Examples:                                                        │   │
│   │    - Cetirizine 20-40mg daily (2-4x)                                │   │
│   │    - Fexofenadine 360-720mg daily (2-4x)                            │   │
│   │    - Bilastine 40-80mg daily (2-4x)                                 │   │
│   │  • Off-label dosing but STRONG guideline recommendation             │   │
│   │  • Response rate: ~60% achieve control                              │   │
│   │  • Assess response: 2-4 weeks                                       │   │
│   │  • Safety: Well-tolerated; minimal sedation even at high doses      │   │
│   └─────────────────────────────────────────────────────────────────────┘   │
│                          ↓ Inadequate control after 2-4 weeks               │
│   ┌─────────────────────────────────────────────────────────────────────┐   │
│   │                 STEP 3: ADD OMALIZUMAB                              │   │
│   │  • Omalizumab (Xolair®) - Anti-IgE monoclonal antibody              │   │
│   │  • Dose: 300mg subcutaneous every 4 weeks                           │   │
│   │  • Continue sgAH (standard or up-dosed)                             │   │
│   │  • Efficacy: ~65-70% achieve complete/near-complete control         │   │
│   │  • Onset: Rapid (often within days to 1-2 weeks)                    │   │
│   │  • Very safe profile (minimal adverse effects)                      │   │
│   │  • Duration: Continue until sustained remission, then trial stop    │   │
│   │  • Assess response: 3-6 months                                      │   │
│   └─────────────────────────────────────────────────────────────────────┘   │
│                          ↓ Inadequate control after 6 months                │
│   ┌─────────────────────────────────────────────────────────────────────┐   │
│   │                 STEP 4: ALTERNATIVE THERAPIES                       │   │
│   │  • Cyclosporin A (Ciclosporin): 3-5 mg/kg/day in 2 divided doses   │   │
│   │    - Efficacy: 60-70% response                                      │   │
│   │    - Monitoring: BP, renal function, drug levels (nephrotoxicity)   │   │
│   │    - Duration: Limited to 3-6 months where possible                 │   │
│   │  • Other options (limited evidence):                                │   │
│   │    - Dapsone, Hydroxychloroquine, Methotrexate, Sulfasalazine      │   │
│   │    - Short-course oral corticosteroids (severe flares only)         │   │
│   │    - H2 antagonists (add-on therapy - limited benefit)              │   │
│   │    - Leukotriene receptor antagonists (montelukast - inconsistent)  │   │
│   └─────────────────────────────────────────────────────────────────────┘   │
│                                                                             │
│   REFRACTORY CASES: Consider specialist immunology/dermatology referral     │
│   Emerging therapies: Ligelizumab, BTK inhibitors, JAK inhibitors          │
│                                                                             │
└─────────────────────────────────────────────────────────────────────────────┘

Step 1: Second-Generation H1-Antihistamines (sgAH)

First-line treatment for all CSU patients. [4,18]

Mechanism of Action

• Selective blockade of H1 receptors on blood vessels, nerves, smooth muscle
• Prevents histamine-induced vasodilation, vascular permeability, pruritus
• Some have additional anti-inflammatory effects (inhibit mediator release)

Recommended Agents (Non-Sedating)

Key Principles:

• Daily dosing (continuous receptor blockade) - NOT "as needed" (PRN)
• All second-generation agents are equally effective at standard doses [18]
• Choice based on availability, cost, patient preference
• Avoid first-generation antihistamines (chlorphenamine, hydroxyzine, diphenhydramine):
  • Cross blood-brain barrier → sedation, impaired driving, cognitive impairment
  • Anticholinergic effects (dry mouth, urinary retention, constipation)
  • REM sleep disruption despite sedation

Assessment: Trial for 2-4 weeks before escalating.

Step 2: Up-Dosing of Second-Generation Antihistamines

Strong evidence supports increasing antihistamine dose up to 4-fold in non-responders. [18,19]

Rationale

• Higher doses achieve greater H1 receptor occupancy
• 60% of standard-dose non-responders achieve control with up-dosing [19]
• Excellent safety profile even at 4x doses

Dosing Examples

Licensing Status:

• Off-label in most countries (licensed dose is standard)
• However, strongly recommended by international guidelines (EAACI, AAAAI) [4,18]
• Well-tolerated and safe in clinical trials

Safety:

• No significant increase in sedation at 4x doses (minimal CNS penetration)
• No cardiotoxicity (unlike terfenadine/astemizole - withdrawn)
• No QT prolongation at recommended doses

Clinical Pearl: Do NOT say "antihistamines don't work" until 4x dosing trialed for at least 2-4 weeks.

Assessment: If inadequate control after 2-4 weeks at up-dosed sgAH → proceed to Step 3.

Step 3: Omalizumab (Anti-IgE Monoclonal Antibody)

Revolutionary treatment for antihistamine-refractory CSU. [20,21]

Mechanism of Action

• Humanized monoclonal antibody against free serum IgE
• Binds to Cε3 domain of IgE → prevents IgE binding to FcεRI (high-affinity receptor) and FcεRII (low-affinity receptor)
• Down-regulates FcεRI expression on mast cells and basophils
• Reduces mast cell sensitivity to activation
• Effective in both Type I (IgE-mediated) and Type IIb (IgG-mediated) autoimmune CSU

Dosing

• 300mg subcutaneously every 4 weeks (standard licensed dose for CSU)
• Pre-filled syringe or vial for injection
• Can be given by healthcare professional or self-administered (trained patients)

Efficacy (GLACIAL, ASTERIA I/II Trials) [20,21]

• Complete response (UAS7 = 0): ~40% at 300mg dose
• Well-controlled (UAS7 ≤6): ~65-70% at 300mg
• Onset: Rapid - often improvement within 1-2 weeks (some respond within days)
• Duration: Continue until disease remission; median treatment duration ~6-12 months
• Relapse: ~50% relapse after stopping, but respond again to re-treatment

Safety

• Excellent safety profile - one of safest biologics
• Most common adverse effects (very mild):
  • Injection site reactions (less than 5%)
  • Headache (10%)
  • Upper respiratory tract infections (comparable to placebo)
• No increased anaphylaxis risk (early concern not confirmed in CSU trials)
• No immunosuppression (unlike ciclosporin)
• Safe in children > 12 years (licensed for CSU from age 12)

Monitoring

• No routine blood monitoring required
• Assess clinical response at 3 and 6 months using UAS7
• If no response at 6 months → consider stopping and moving to Step 4

Cost Considerations

• Expensive (£££) - requires specialist approval in most healthcare systems
• Cost-effectiveness demonstrated for severe, refractory CSU [8]
• Biosimilars emerging (may improve accessibility)

Clinical Pearl: Omalizumab is effective regardless of total IgE level or ASST result. Do NOT withhold based on low IgE.

Step 4: Ciclosporin and Alternative Immunosuppressants

For the small minority who fail omalizumab:

Ciclosporin (Cyclosporin A) [22]

• Mechanism: Calcineurin inhibitor → suppresses T-cell activation and cytokine production
• Dose: 3-5 mg/kg/day in 2 divided doses (starting 3 mg/kg, increase if needed)
• Efficacy: 60-70% response rate; onset 2-4 weeks
• Duration: Limit to 3-6 months where possible (long-term toxicity risk)
• Monitoring:
  • "Baseline: BP, renal function (creatinine, eGFR), liver function"
  • "Every 2 weeks initially, then monthly: BP, creatinine"
  • Ciclosporin levels not routinely required in CSU
• Adverse Effects:
  • Hypertension (20-30%) - dose-related, reversible
  • Nephrotoxicity (dose-dependent; monitor creatinine)
  • Gingival hyperplasia, hirsutism, tremor
  • Increased infection risk (modest)
  • Drug interactions (metabolized by CYP3A4)
• Contraindications: Uncontrolled hypertension, significant renal impairment, malignancy, pregnancy

Other Immunosuppressants (Limited Evidence)

• Methotrexate: 10-15 mg weekly (case series; inconsistent results)
• Dapsone: 50-150 mg daily (may help in autoimmune CSU)
• Hydroxychloroquine: 200 mg daily (anti-inflammatory; case reports)
• Sulfasalazine: 2-3 g daily (anti-inflammatory)
• Mycophenolate mofetil: 1-2 g daily (case reports)

Evidence: All have limited, low-quality evidence; used as last resort.

Adjunctive and Short-Term Therapies

Short-Course Oral Corticosteroids

• Indication: Severe exacerbations only (NOT maintenance)
• Dose: Prednisolone 20-40 mg daily for 3-7 days
• Rationale: Rapid symptom control during flares
• Avoid: Long-term use (> 2 weeks) due to:
  • Adrenal suppression
  • Weight gain, diabetes, osteoporosis
  • Hypertension, mood changes, gastritis
• EAACI recommendation: Avoid corticosteroids for chronic use (strong recommendation AGAINST) [4]

H2-Receptor Antagonists (Add-On)

• Agents: Ranitidine (withdrawn), famotidine, cimetidine
• Rationale: Block H2 receptors (complement H1 blockade)
• Evidence: Minimal added benefit in CSU; not routinely recommended [4]
• Possible use: Severe cases as add-on to sgAH

Leukotriene Receptor Antagonists (LTRAs)

• Agent: Montelukast 10 mg OD
• Rationale: Block leukotriene effects (vascular permeability)
• Evidence: Inconsistent; some benefit in NSAID-exacerbated CSU or cholinergic urticaria [23]
• EAACI recommendation: Weak evidence; may consider as add-on

Tranexamic Acid

• Rationale: Inhibits plasmin (part of coagulation-inflammation axis in CSU)
• Evidence: Limited case reports
• Not routinely recommended

Avoid Therapies with NO Evidence

• ❌ Antihistamine combinations (mixing different classes): No added benefit over up-dosing single agent
• ❌ Long-term steroids: Harm outweighs benefit
• ❌ Food elimination diets: Not evidence-based (exception: pseudo-allergen-free diet in selected cases)
• ❌ Vitamin D supplementation: Inconsistent evidence (unless deficient)

Emerging and Future Therapies

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6. Special Scenarios

Angioedema Without Wheals

If patient has angioedema ONLY (no urticarial wheals), consider alternative diagnoses:

1. ACE Inhibitor-Induced Angioedema [24]

• Mechanism: ACE inhibitors prevent bradykinin degradation → increased vascular permeability
• Onset: Can occur years after starting ACEi (not just at initiation)
• Features:
  • Non-pruritic swelling (lips, tongue, face, larynx)
  • NO wheals
  • Does NOT respond to antihistamines, steroids, or adrenaline
• Management:
  • Stop ACE inhibitor immediately (switch to ARB - lower risk but can still occur)
  • "Acute severe: Fresh frozen plasma (FFP), icatibant (bradykinin B2 receptor antagonist)"
  • Airway management if laryngeal involvement

2. Hereditary Angioedema (HAE) [25]

• Mechanism: C1-esterase inhibitor (C1-INH) deficiency (Type I/II) or dysfunction (Type III)
• Features:
  • Recurrent angioedema (face, extremities, genitals, gastrointestinal tract, larynx)
  • NO wheals or pruritus
  • Abdominal pain (intestinal wall edema) - may mimic acute abdomen
  • Family history (autosomal dominant) - but 25% are de novo mutations
  • Onset childhood/adolescence
• Triggers: Trauma, stress, surgery, menstruation, ACE inhibitors
• Diagnosis:
  • "C4 level: Low/undetectable (excellent screening test - if normal, HAE excluded)"
  • "C1-INH level: Low (Type I HAE - 85%) or normal (Type II HAE - 15%)"
  • "C1-INH function: Low in both Type I and II"
• Management:
  • "Acute attack: "
    • C1-INH concentrate (Berinert, Cinryze) - IV
    • Icatibant (bradykinin B2 antagonist) - SC
    • Ecallantide (kallikrein inhibitor) - SC
  • "Prophylaxis: "
    • C1-INH replacement (regular IV infusions)
    • Androgens (danazol, stanozolol) - increase C1-INH synthesis
    • Tranexamic acid (antifibrinolytic)
  • "Antihistamines, steroids, adrenaline: INEFFECTIVE"

Red Flag: Isolated angioedema + normal C4 → likely ACEi-induced (if on ACEi) or acquired angioedema (AAE)

Urticarial Vasculitis [17]

A distinct entity mimicking urticaria but with vasculitic pathology.

Clinical Features Distinguishing from CSU:

• Individual lesions persist > 24 hours (often 24-72h)
• Painful or burning rather than itchy
• Leave purpura or hyperpigmentation when resolving (post-inflammatory change)
• Associated systemic features:
  • Arthralgia/arthritis (70%)
  • Fever, malaise
  • Hypocomplementemia (low C3/C4) - if present, termed "hypocomplementemic urticarial vasculitis" (HUVS)
  • Renal involvement (20% HUVS)
  • Pulmonary involvement (dyspnea, restrictive lung disease)

Associations:

• Systemic Lupus Erythematosus (SLE) - most common
• Sjögren's syndrome
• Hepatitis B/C
• Paraproteinemia

Diagnosis:

• Skin biopsy (essential):
  • Leukocytoclastic vasculitis (fibrinoid necrosis, neutrophil infiltration, red cell extravasation)
  • "Direct immunofluorescence: IgG, IgM, C3 deposition in vessel walls"
• Blood tests:
  • Low C3, C4 (HUVS)
  • Elevated ESR/CRP
  • ANA, anti-dsDNA (if SLE suspected)

Management:

• NOT responsive to standard CSU management
• Treat underlying cause (e.g., SLE)
• Immunosuppression: Hydroxychloroquine, dapsone, colchicine, systemic steroids, azathioprine
• Refer to rheumatology/dermatology

CSU in Pregnancy [26]

Safety of Antihistamines in Pregnancy:

Recommendations:

• First-line: Cetirizine or loratadine at standard doses
• Avoid: Up-dosing in pregnancy (lack of safety data; use lowest effective dose)
• Omalizumab: Limited data; case reports suggest safety, but manufacturer recommends caution (Pregnancy Category B)
• Ciclosporin: Contraindicated (teratogenic risk)
• Corticosteroids: Avoid if possible (short-term use for severe exacerbation only - prednisolone preferred over dexamethasone/betamethasone due to placental metabolism)

Spontaneous improvement: CSU may improve in pregnancy (immunological changes), but can also worsen postpartum.

CSU in Children [27]

• Prevalence: Less common than adults; 0.1-0.3% of children
• Management: Similar stepwise approach as adults
• Dosing: Adjusted for age/weight
  • "Cetirizine syrup: 0.25 mg/kg/dose (6 months-5 years: 2.5-5 mg OD; > 6 years: 5-10 mg OD)"
  • "Loratadine syrup: 5 mg OD (less than 30 kg), 10 mg OD (> 30 kg)"
• Omalizumab: Licensed from age 12 for CSU (300 mg monthly)
• Prognosis: Better than adults; higher rate of spontaneous remission

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7. Prognosis and Quality of Life

Natural History [6]

Factors predicting longer duration:

• Severe disease (high UAS7)
• Presence of angioedema
• Positive ASST (autoimmune CSU)
• Elevated inflammatory markers (ESR/CRP)
• Thyroid autoimmunity

Quality of Life Impact [7]

CSU has profound impact on quality of life:

• Sleep disturbance: Nocturnal pruritus → insomnia, fatigue (> 70% patients)
• Psychological: Anxiety (48%), depression (30%), social embarrassment
• Functional: Impaired work/school performance, absenteeism
• Sexual health: Reduced libido, relationship strain
• DLQI scores: Comparable to ischemic heart disease or severe psoriasis (mean DLQI 10-12)

Validated tools:

• UAS7: Disease activity
• DLQI (Dermatology Life Quality Index): QoL impact
• CU-Q2oL (Chronic Urticaria Quality of Life Questionnaire): CSU-specific QoL

Treatment goal: Achieve complete symptom control (UAS7 = 0) to restore quality of life.

Complications

• Sleep deprivation: Chronic insomnia, daytime fatigue
• Psychological morbidity: Anxiety, depression (screen with PHQ-9, GAD-7)
• Impaired school/work performance: Absenteeism, reduced productivity
• Iatrogenic complications: Systemic toxicity from inappropriate long-term corticosteroid use (avoidable)

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8. Key Clinical Pearls

Exam-Focused Points (MRCP, Dermatology)

1. CSU is NOT allergic: Extensive allergy testing is NOT indicated. It is an autoimmune condition with spontaneous mast cell activation. Counsel patients accordingly.

2. 4x antihistamine dosing: Do NOT say "antihistamines failed" until up-dosing to 4-fold standard dose for 2-4 weeks. This is a strong guideline recommendation.

3. Omalizumab is highly effective: 65-70% response rate in antihistamine-refractory CSU. Safe and well-tolerated. Effective regardless of IgE level.

4. Wheals last less than 24 hours: Individual lesions resolving within 24h is a diagnostic criterion. If > 24h → think urticarial vasculitis (requires biopsy).

5. Screen for thyroid disease: 15-30% have anti-TPO antibodies. Check TSH and anti-TPO at baseline. However, treating thyroid disease does NOT cure CSU.

6. ACE inhibitors: In isolated angioedema (no wheals), ask about ACE inhibitor use. Can occur years after starting. Stop immediately.

7. C4 level: The screening test for Hereditary Angioedema (in isolated angioedema without wheals). If C4 normal → HAE excluded.

8. Avoid NSAIDs: Worsen CSU in 20-30% of patients (pseudo-allergen effect, direct mast cell activation). Use paracetamol instead.

9. Avoid long-term steroids: Strong recommendation AGAINST maintenance corticosteroids. Use only for short-term (3-7 days) severe exacerbations.

10. UAS7 scoring: Gold-standard severity assessment (range 0-42). Target UAS7 ≤6 for well-controlled disease. Required for omalizumab funding.

Common Exam Scenarios

Scenario 1: Patient with 3 months of daily hives

• Patient asks: "Do I need allergy testing?"
• Answer:
  • Explain autoimmune nature (not external allergy)
  • Start daily second-generation antihistamine
  • Routine baseline bloods (FBC, ESR, thyroid)
  • Avoid extensive allergy panels (low yield)

Scenario 2: Patient on fexofenadine 180mg OD still symptomatic

• Next step:
  • Up-dose to 360 mg daily (2x) or 720 mg daily (4x) - off-label but guideline-recommended
  • Assess for 2-4 weeks
  • If still inadequate → omalizumab

Scenario 3: Patient with lip swelling, no wheals, taking ramipril for 5 years

• Diagnosis: ACE inhibitor-induced angioedema
• Management:
  • Stop ramipril immediately
  • "Switch to ARB (caution: 10% cross-reactivity) or alternative antihypertensive"
  • Antihistamines will NOT help (bradykinin-mediated)
  • If severe → FFP, icatibant (specialist)

Scenario 4: Urticaria patient with painful lesions lasting 48h, leaving bruises

• Diagnosis: Urticarial vasculitis (NOT CSU)
• Investigations:
  • Skin biopsy (leukocytoclastic vasculitis)
  • Complement (C3, C4), ESR, CRP
  • ANA, ENA (SLE screen)
• Management: Immunosuppression (not standard CSU treatment); rheumatology referral

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9. Patient Explanation

What is Chronic Spontaneous Urticaria?

"Chronic spontaneous urticaria is a condition where your skin's immune cells, called mast cells, become 'overactive' and release chemicals like histamine too easily. This causes the red, itchy bumps (wheals or hives) and sometimes swelling.

Unlike acute hives from something like a peanut allergy, chronic urticaria is not caused by something you're eating, touching, or breathing in. It's an internal immune problem - your immune system is activating your mast cells by mistake. This is why finding a specific 'allergy' is unlikely, and allergy testing is usually not helpful."

Why Did I Get This?

"In many people, chronic urticaria is autoimmune - meaning your immune system makes antibodies that mistakenly activate your own mast cells. We don't fully understand why this happens, but it's similar to other autoimmune conditions.

It's more common in women and often linked to other autoimmune problems, especially thyroid disease. We'll check your thyroid as part of the workup."

Will It Go Away?

"Yes, for most people it eventually resolves on its own - but this can take time. About half of people improve within a year, and 80% are better within 5 years. However, it's unpredictable.

Our goal is to completely control your symptoms with medication while we wait for it to burn itself out, so you can live a normal life without hives and itching."

What Are the Treatment Options?

"We use a step-by-step approach:

1. Antihistamine tablets daily - this is the first step. You need to take them every day (not just when you have hives) to keep histamine blocked all the time.

2. Higher doses of antihistamines - if standard doses don't work, we can safely increase the dose up to 4 times the normal amount. Modern antihistamines are very safe even at high doses.

3. Omalizumab injections - if high-dose antihistamines aren't enough, we have a very effective injection treatment called omalizumab. You get an injection once a month under the skin. It works by reducing the IgE in your blood, which makes mast cells less sensitive. It's very safe and works in about 7 out of 10 people who haven't responded to antihistamines.

4. Other medications - for the rare person who doesn't respond to omalizumab, there are other options like immunosuppressant tablets."

Is the Medication Safe?

"Yes. Modern antihistamines are very safe, even when we use higher doses. They do not cause harm to your organs, and they are not addictive. They're much safer than taking steroid tablets long-term.

Omalizumab is also very safe - it's one of the safest biologic medications we use. Most people have no side effects at all, or just mild things like a mild headache."

What Should I Avoid?

"1. NSAIDs/anti-inflammatories (like ibuprofen, aspirin): These can make chronic urticaria worse in about 1 in 3 people. Use paracetamol for pain relief instead.

2. Stopping your antihistamine suddenly: Even if you feel better, keep taking it daily until we advise you to stop - otherwise the hives usually come back.

3. Searching for a food allergy: Extensive food elimination is usually unhelpful and stressful. Only consider this if there's a clear pattern."

When Should I Seek Urgent Help?

"Go to A&E immediately if you develop:

• Swelling of your tongue or throat with difficulty breathing or swallowing
• Stridor (noisy breathing)
• Dizziness, collapse, or widespread body reaction (which might be anaphylaxis - very rare in chronic urticaria)"

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10. Examination Viva Scenarios

Scenario 1: Data Interpretation

Examiner: "A 32-year-old woman presents with 4 months of daily itchy wheals. Investigations show: FBC normal, ESR 5, TSH 6.2 (high), anti-TPO antibodies positive. What is the significance of the thyroid results?"

Model Answer: "The results show subclinical hypothyroidism with positive anti-TPO antibodies, indicating autoimmune thyroid disease (likely Hashimoto's thyroiditis).

Significance:

1. Autoimmune association: 15-30% of CSU patients have thyroid autoimmunity. This reflects a shared autoimmune susceptibility but is not directly causal of the urticaria.
2. Does NOT change CSU management: Treating the thyroid disorder (e.g., with levothyroxine if indicated) will not cure the urticaria, but it's important to manage the thyroid condition in its own right.
3. Prognosis: Positive autoimmune markers may be associated with longer urticaria duration and more severe disease.

Management: Start standard CSU treatment (daily second-generation antihistamine). Consider levothyroxine if TSH remains elevated on repeat testing (as per hypothyroidism guidelines). Monitor thyroid function."

Scenario 2: Management Challenge

Examiner: "A 45-year-old man with CSU has been on cetirizine 40mg daily for 6 weeks with minimal improvement. UAS7 score is 28 (severe). What are your next steps?"

Model Answer: "This patient has severe, antihistamine-refractory CSU (failed up-dosed second-generation antihistamine).

Next steps (STEP 3: Omalizumab):

1. Add omalizumab 300 mg subcutaneous every 4 weeks

   • Continue cetirizine alongside
   • Highly effective: ~65-70% achieve control (UAS7 ≤6)
   • Very safe profile
   • Onset often within 1-2 weeks

2. Monitoring:

   • Reassess UAS7 at 3 and 6 months
   • No routine blood tests required
   • If no response by 6 months → consider alternative therapies (Step 4)

3. Patient counseling:

   • Explain injection schedule (monthly)
   • Set realistic expectations (most respond but not all)
   • Advise continuing daily antihistamine
   • Duration: Ongoing until sustained remission achieved

Alternative if omalizumab unavailable/contraindicated: Consider ciclosporin 3-5 mg/kg/day (requires monitoring for BP and renal function)."

Scenario 3: Differential Diagnosis

Examiner: "A 50-year-old woman presents with recurrent 'urticaria' - but the lesions are painful, last 2-3 days, and leave brown marks. She also has joint pains. What is your differential and how would you investigate?"

Model Answer: "The clinical features are NOT consistent with chronic spontaneous urticaria. The key distinguishing features are:

• Lesions lasting > 24 hours
• Pain (not pruritus)
• Residual pigmentation (post-inflammatory change)
• Systemic symptoms (arthralgia)

Top differential: Urticarial Vasculitis

Investigations:

1. Skin biopsy (essential):
   • Lesional biopsy showing leukocytoclastic vasculitis
   • Direct immunofluorescence (IgG/C3 deposition)
2. Blood tests:
   • Complement levels (C3, C4): Low in hypocomplementemic urticarial vasculitis (HUVS)
   • ESR/CRP: Elevated (vasculitis/inflammation)
   • ANA, anti-dsDNA, ENA: Screen for SLE (commonest association)
3. Urinalysis: Proteinuria/hematuria (renal involvement in HUVS)
4. Hepatitis B/C serology: Vasculitis trigger

Management:

• NOT standard CSU treatment (antihistamines ineffective)
• Treat underlying cause (e.g., SLE)
• Immunosuppression: Hydroxychloroquine, dapsone, colchicine, systemic steroids
• Refer to rheumatology"

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11. Evidence & Guidelines

Key Guidelines

Landmark Trials and Evidence

Omalizumab Efficacy Trials

GLACIAL, ASTERIA I, ASTERIA II (2013-2014) [20,21]

• Design: Randomized, double-blind, placebo-controlled Phase III trials
• Population: Antihistamine-refractory CSU (failed up-dosed sgAH)
• Intervention: Omalizumab 75mg, 150mg, or 300mg SC every 4 weeks vs. placebo (+ background sgAH)
• Primary outcome: Change in UAS7 from baseline to week 12
• Results:
  • "300mg dose: "
    • Mean UAS7 reduction: -20 to -23 points (vs. -9 placebo)
    • Complete response (UAS7=0): 36-44% (vs. 5-9% placebo)
    • Well-controlled (UAS7 ≤6): ~65% (vs. 15% placebo)
  • "Dose-response: 300mg superior to 150mg and 75mg"
  • "Onset: Improvement within 1-2 weeks"
  • "Safety: Excellent; no increased serious adverse events"
• Impact: Led to FDA/EMA approval of omalizumab 300mg monthly for CSU (2014)

Antihistamine Up-Dosing Studies

Systematic reviews and meta-analyses (2016-2019) [19]

• Finding: Up-dosing sgAH to 4-fold increases response rate from ~40% to ~60-65%
• Safety: No significant increase in sedation or adverse events at 4x doses
• Guideline impact: Strong recommendation for Step 2 up-dosing before advancing to omalizumab

Autoimmune Mechanisms

Hide et al. (1993), Sabroe et al. (1999) [10,11]

• Autologous Serum Skin Test (ASST): Identified functional histamine-releasing autoantibodies in 40-50% CSU patients
• IgG anti-FcεRI antibodies: Characterized Type IIb autoimmune mechanism
• Clinical significance: ASST-positive patients have more severe, longer-lasting disease

Quality of Life Studies

Baiardini et al. (2006), O'Donnell et al. (2018) [7]

• DLQI scores: Mean 10-12 in CSU (moderate-severe impact)
• Comparison: QoL impairment comparable to ischemic heart disease, severe psoriasis
• Sleep: Nocturnal pruritus leads to insomnia in > 70%
• Psychological: Depression (30%), anxiety (48%)
• Impact of omalizumab: Significant improvement in DLQI and CU-Q2oL scores with treatment

Evidence-Based Recommendations Summary

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12. References

1. Zuberbier T, Abdul Latiff AH, Abuzakouk M, et al. The international EAACI/GA²LEN/EuroGuiDerm/APAAACI guideline for the definition, classification, diagnosis, and management of urticaria. Allergy. 2022;77(3):734-766. doi:10.1111/all.15090

2. Maurer M, Weller K, Bindslev-Jensen C, et al. Unmet clinical needs in chronic spontaneous urticaria. A GA²LEN task force report. Allergy. 2011;66(3):317-330. doi:10.1111/j.1398-9995.2010.02496.x

3. Kolkhir P, Church MK, Weller K, Metz M, Schmetzer O, Maurer M. Autoimmune chronic spontaneous urticaria: What we know and what we do not know. J Allergy Clin Immunol. 2017;139(6):1772-1781. doi:10.1016/j.jaci.2016.08.050

4. Zuberbier T, Aberer W, Asero R, et al. The EAACI/GA²LEN/EDF/WAO guideline for the definition, classification, diagnosis and management of urticaria. Allergy. 2018;73(7):1393-1414. doi:10.1111/all.13397

5. Fricke J, Ávila G, Keller T, et al. Prevalence of chronic urticaria in children and adults across the globe: Systematic review with meta-analysis. Allergy. 2020;75(2):423-432. doi:10.1111/all.14037

6. Toubi E, Kessel A, Avshovich N, et al. Clinical and laboratory parameters in predicting chronic urticaria duration: a prospective study of 139 patients. Allergy. 2004;59(8):869-873. doi:10.1111/j.1398-9995.2004.00473.x

7. O'Donnell BF, Lawlor F, Simpson J, Morgan M, Greaves MW. The impact of chronic urticaria on the quality of life. Br J Dermatol. 1997;136(2):197-201. PMID: 9068731

8. Balp MM, Vietri J, Tian H, Isherwood G. The impact of chronic urticaria from the patient's perspective: a survey in five European countries. Patient. 2015;8(6):551-558. doi:10.1007/s40271-015-0145-9

9. Kaplan AP, Greaves M. Pathogenesis of chronic urticaria. Clin Exp Allergy. 2009;39(6):777-787. doi:10.1111/j.1365-2222.2009.03256.x

10. Sabroe RA, Grattan CE, Francis DM, Barr RM, Kobza Black A, Greaves MW. The autologous serum skin test: a screening test for autoantibodies in chronic idiopathic urticaria. Br J Dermatol. 1999;140(3):446-452. PMID: 10233264

11. Hide M, Francis DM, Grattan CE, Hakimi J, Kochan JP, Greaves MW. Autoantibodies against the high-affinity IgE receptor as a cause of histamine release in chronic urticaria. N Engl J Med. 1993;328(22):1599-1604. doi:10.1056/NEJM199306033282204

12. Asero R, Tedeschi A, Coppola R, et al. Activation of the tissue factor pathway of blood coagulation in patients with chronic urticaria. J Allergy Clin Immunol. 2007;119(3):705-710. doi:10.1016/j.jaci.2006.08.043

13. Confino-Cohen R, Chodick G, Shalev V, Leshno M, Kimhi O, Goldberg A. Chronic urticaria and autoimmunity: associations found in a large population study. J Allergy Clin Immunol. 2012;129(5):1307-1313. doi:10.1016/j.jaci.2012.01.043

14. Asero R. Intolerance to nonsteroidal anti-inflammatory drugs might precede by years the onset of chronic urticaria. J Allergy Clin Immunol. 2003;111(5):1095-1098. doi:10.1067/mai.2003.1448

15. Hawro T, Ohanyan T, Schoepke N, et al. Comparison and interpretability of the available urticaria activity scores. Allergy. 2018;73(2):251-255. doi:10.1111/all.13271

16. Federman DG, Kirsner RS, Moriarty JP, Concato J. The effect of antibiotic therapy for patients infected with Helicobacter pylori who have chronic urticaria. J Am Acad Dermatol. 2003;49(5):861-864. doi:10.1016/S0190-9622(03)02478-0

17. Davis MD, Brewer JD. Urticarial vasculitis and hypocomplementemic urticarial vasculitis syndrome. Immunol Allergy Clin North Am. 2004;24(2):183-213. doi:10.1016/j.iac.2004.01.007

18. Zuberbier T, Balke M, Worm M, Edenharter G, Maurer M. Epidemiology of urticaria: a representative cross-sectional population survey. Clin Exp Dermatol. 2010;35(8):869-873. doi:10.1111/j.1365-2230.2010.03840.x

19. Sharma M, Bennett C, Carter B, Cohen SN. H1-antihistamines for chronic spontaneous urticaria: an abridged Cochrane Systematic Review. J Am Acad Dermatol. 2015;73(4):710-716. doi:10.1016/j.jaad.2015.06.048

20. Maurer M, Rosén K, Hsieh HJ, et al. Omalizumab for the treatment of chronic idiopathic or spontaneous urticaria. N Engl J Med. 2013;368(10):924-935. doi:10.1056/NEJMoa1215372

21. Kaplan A, Ledford D, Ashby M, et al. Omalizumab in patients with symptomatic chronic idiopathic/spontaneous urticaria despite standard combination therapy. J Allergy Clin Immunol. 2013;132(1):101-109. doi:10.1016/j.jaci.2013.05.013

22. Grattan CE, O'Donnell BF, Francis DM, et al. Randomized double-blind study of cyclosporin in chronic 'idiopathic' urticaria. Br J Dermatol. 2000;143(2):365-372. PMID: 10951147

23. Di Lorenzo G, Pacor ML, Mansueto P, et al. Randomized placebo-controlled trial comparing desloratadine and montelukast in monotherapy and desloratadine plus montelukast in combined therapy for chronic idiopathic urticaria. J Allergy Clin Immunol. 2004;114(3):619-625. doi:10.1016/j.jaci.2004.06.018

24. Banerji A, Clark S, Blanda M, LoVecchio F, Snover W, Camargo CA. Multicenter study of patients with angiotensin-converting enzyme inhibitor-induced angioedema who present to the emergency department. Ann Allergy Asthma Immunol. 2008;100(4):327-332. doi:10.1016/S1081-1206(10)60594-7

25. Cicardi M, Aberer W, Banerji A, et al. Classification, diagnosis, and approach to treatment for angioedema: consensus report from the Hereditary Angioedema International Working Group. Allergy. 2014;69(5):602-616. doi:10.1111/all.12380

26. Namazy J, Cabana MD, Scheuerle AE, et al. The Xolair Pregnancy Registry (EXPECT): the safety of omalizumab use during pregnancy. J Allergy Clin Immunol. 2015;135(2):407-412. doi:10.1016/j.jaci.2014.08.025

27. Caffarelli C, Cuomo B, Cardinale F, et al. Aetiological factors associated with chronic urticaria in children: a systematic review. Acta Derm Venereol. 2013;93(3):268-272. doi:10.2340/00015555-1511

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13. Summary - High-Yield Facts

Definition: Wheals (±angioedema) for > 6 weeks; CSU = no external trigger.

Pathophysiology: Autoimmune mast cell/basophil activation (Type I IgE auto-antibodies 40-50%; Type IIb IgG anti-FcεRI/anti-IgE 30-40%).

Clinical Features: Transient itchy wheals (less than 24h duration); angioedema in 40%; migratory pattern.

UAS7: Validated severity score (0-42); wheals + pruritus daily for 7 days; target ≤6.

Investigations: Minimal routine workup (FBC, ESR, TSH, anti-TPO); avoid extensive allergy tests.

Management:

• Step 1: sgAH daily (cetirizine, fexofenadine, bilastine)
• Step 2: Up-dose sgAH to 4x (off-label, guideline-recommended)
• Step 3: Omalizumab 300mg SC monthly (~70% response)
• Step 4: Ciclosporin 3-5 mg/kg/day (requires monitoring)

Avoid: Long-term steroids (strong recommendation AGAINST); NSAIDs (worsen CSU).

Prognosis: 50% remission by 1 year; 20% persist > 5 years.

Associations: Thyroid autoimmunity (15-30%); other autoimmune diseases.

Differentials: Urticarial vasculitis (painful, > 24h, purpura); HAE (isolated angioedema, low C4); ACEi angioedema.

QoL Impact: Comparable to ischemic heart disease; severe sleep disruption.

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