# Urticaria and Angioedema

## Classification

Urticaria is classified primarily by duration and etiology. Acute urticaria, defined as wheals lasting less than 6 weeks in total duration, is the most common form. Causes include infections (viral infections being the most common trigger in children), foods, medications, Hymenoptera stings, and idiopathic etiologies. Most cases of acute urticaria resolve spontaneously. Chronic urticaria is defined as wheals occurring on most days of the week for 6 weeks or longer and is further subdivided into chronic spontaneous urticaria (CSU), in which no identifiable external trigger is found and which accounts for approximately 70 percent of chronic urticaria cases, and chronic inducible urticaria (CIndU), in which wheals are triggered by specific reproducible physical stimuli.

A fundamental clinical characteristic is that individual wheals in urticaria are transient, with each wheal lasting less than 24 hours and resolving without residual marks. If individual lesions persist beyond 24 hours or leave bruising or hyperpigmentation, the diagnosis of urticarial vasculitis should be considered and biopsy pursued.

## Chronic Spontaneous Urticaria (CSU)

### Epidemiology

Chronic spontaneous urticaria has a point prevalence of 0.5 to 1 percent of the population, with a female predominance of approximately 2:1 and peak incidence between ages 20 and 40. The natural history is variable: the median duration is 3 to 5 years, approximately 50 percent of patients achieve remission within 5 years, but 20 percent continue to experience symptoms beyond 10 years. The impact on quality of life is substantial, with studies demonstrating impairment comparable to that of coronary artery disease.

### Pathophysiology

Chronic spontaneous urticaria is fundamentally a mast cell-centric disease characterized by spontaneous mast cell activation in the skin. Two autoimmune subtypes have been delineated. Type I autoimmune CSU, also termed autoallergic CSU, is driven by IgE autoantibodies directed against self-antigens, including anti-thyroid peroxidase (TPO) IgE, anti-IL-24 IgE, and anti-double-stranded DNA IgE. In this mechanism, the self-antigen crosslinks IgE bound to mast cell FcepsilonRI, mirroring the mechanism of classical allergen-driven mast cell activation. This subtype characteristically responds well to omalizumab, which removes circulating IgE.

Type IIb autoimmune CSU is driven by IgG autoantibodies directed against IgE itself or against FcepsilonRI on mast cells. These autoantibodies directly crosslink receptors, causing mast cell degranulation without the need for an allergen bridge. This subtype can be detected by the autologous serum skin test (ASST) or the basophil histamine release assay (BHRA), and tends to be less responsive to omalizumab but may respond to cyclosporine. Non-autoimmune CSU encompasses cases with unclear mechanisms, potentially involving mast cell-intrinsic defects or neurogenic inflammation.

Additional pathophysiologic features include activation of complement and coagulation pathways, with elevated D-dimer and prothrombin fragment F1+2 levels correlating with disease severity. Autoimmune comorbidities are common, with 10 to 30 percent of CSU patients harboring anti-thyroid antibodies, and associations with vitiligo and type 1 diabetes reported.

### Diagnosis

The diagnosis of CSU is clinical, based on the presence of characteristic wheals with or without angioedema occurring for 6 weeks or longer. Each wheal must be transient (lasting less than 24 hours), migratory, and pruritic (not painful). Angioedema accompanies wheals in approximately 40 percent of CSU patients, commonly affecting the lips, eyelids, hands, feet, and genitals. The recommended laboratory workup is deliberately minimal: a complete blood count with differential and ESR or CRP to screen for underlying inflammatory or hematologic conditions. Optional testing may include total IgE (which can predict omalizumab response, with low IgE potentially predicting slower response), thyroid function and anti-thyroid antibodies, ANA, and baseline tryptase if mast cell disease is suspected (a level exceeding 11.4 ng/mL warranting further evaluation). Skin biopsy is not routine but is indicated when wheals last beyond 24 hours, are painful rather than pruritic, leave residual bruising, or the patient responds poorly to antihistamine therapy, all of which should raise suspicion for urticarial vasculitis. A critical principle is that exhaustive allergen testing panels should not be pursued, as CSU is not caused by food allergies.

### Assessment Tools

Disease activity and treatment response in CSU are monitored using validated instruments. The UAS7 (Urticaria Activity Score 7) is calculated by summing daily scores for wheal number (0 to 3) and pruritus intensity (0 to 3) over seven days, yielding a range of 0 to 42. Scores are interpreted as: 0 (urticaria-free), 1 to 6 (well-controlled), 7 to 15 (mild), 16 to 27 (moderate), and 28 to 42 (severe). The UCT (Urticaria Control Test) consists of 4 questions, with a score of 12 or above indicating well-controlled disease and below 12 indicating poorly controlled disease. The AAS (Angioedema Activity Score) is used for patients with angioedema as a predominant feature.

| UAS7 Score | Interpretation |
|---|---|
| 0 | Urticaria-free |
| 1-6 | Well-controlled |
| 7-15 | Mild |
| 16-27 | Moderate |
| 28-42 | Severe |

<image>A diagnostic and classification flowchart for urticaria and angioedema. Starting point: "Wheals (urticaria) and/or angioedema." First decision: "Duration <6 weeks?" If Yes: Acute urticaria - evaluate for triggers (foods, drugs, infections, venom). If No (>=6 weeks): Chronic urticaria. Branch: "Triggered by identifiable physical stimulus?" If Yes: Chronic inducible urticaria - subtype testing (dermographism, cold, pressure, solar, cholinergic, aquagenic, vibratory). If No: Chronic spontaneous urticaria - subclassify as Type I autoimmune (IgE autoantibodies, high total IgE, ASST negative, omalizumab-responsive) vs Type IIb autoimmune (IgG anti-FcepsilonRI/IgE, ASST positive, low IgE, omalizumab-resistant, cyclosporine-responsive) vs non-autoimmune. Side panel: "Red flags requiring biopsy" - wheals >24h, painful, leave bruising, elevated ESR, hypocomplementemia (urticarial vasculitis).</image>

## Treatment of CSU

### Step 1: Second-Generation H1 Antihistamine (Standard Dose)

First-line therapy for CSU is a second-generation H1 antihistamine at standard dose, with options including cetirizine 10 mg, levocetirizine 5 mg, loratadine 10 mg, desloratadine 5 mg, fexofenadine 180 mg, bilastine 20 mg, or rupatadine 10 mg. Approximately 40 to 50 percent of patients achieve adequate control at standard doses. First-generation H1 antihistamines should be avoided as maintenance therapy due to their sedative and anticholinergic effects, impaired driving performance, and cognitive impairment.

### Step 2: Updosed Second-Generation H1 Antihistamine (Up to 4x Standard Dose)

For patients not controlled on standard-dose antihistamines, international guidelines from EAACI, GA2LEN, EDF, and WAO recommend increasing the dose up to four times the standard dose. Examples include cetirizine 40 mg daily or fexofenadine 720 mg daily. While off-label, this approach is well-supported by clinical evidence and increases the response rate to approximately 60 to 70 percent, with an additional 15 to 25 percent of patients responding to the higher doses.

### Step 3: Omalizumab (Xolair)

For patients remaining symptomatic despite updosed antihistamines, omalizumab, an anti-IgE monoclonal antibody, is approved for CSU in patients aged 12 years and older. Dosing for CSU uses fixed doses of 150 mg or 300 mg subcutaneously every 4 weeks, notably not based on IgE level or body weight (unlike its asthma indication). The ASTERIA I, ASTERIA II, and GLACIAL trials demonstrated significant reductions in UAS7 scores, with 50 to 70 percent of patients achieving a UAS7 of 6 or below and approximately 35 percent achieving complete response (UAS7 of 0).

The response pattern to omalizumab provides mechanistic insight. Fast responders, who improve within 1 to 2 weeks, likely represent the autoallergic (Type I autoimmune) subtype, where rapid removal of circulating IgE interrupts the pathogenic mechanism. Slow responders, who improve gradually over 3 to 6 months, likely benefit from the downstream effect of FcepsilonRI downregulation on mast cells. Approximately 15 to 25 percent of patients are non-responders, and these likely have Type IIb autoimmune CSU driven by IgG autoantibodies that are not addressed by IgE removal. Relapse upon omalizumab discontinuation is common, and many patients require long-term treatment. The medication is well tolerated with no required laboratory monitoring.

### Step 4: Add-on to Omalizumab or Alternative

| Step | Therapy | Details |
|---|---|---|
| 1 | Second-generation H1 antihistamine (standard dose) | Cetirizine 10 mg, levocetirizine 5 mg, loratadine 10 mg, desloratadine 5 mg, fexofenadine 180 mg; ~40-50% response |
| 2 | Updosed H1 antihistamine (up to 4x dose) | Cetirizine 40 mg or fexofenadine 720 mg daily; ~60-70% cumulative response |
| 3 | Omalizumab (Xolair) | 150 or 300 mg SC q4 weeks (fixed dose, not weight/IgE-based); 50-70% achieve UAS7 ≤6 |
| 4 | Cyclosporine A or alternative | Cyclosporine 3-5 mg/kg/day (60-70% response in refractory); or montelukast, dapsone, BTK inhibitors |

For omalizumab-refractory CSU, cyclosporine A at 3 to 5 mg/kg/day is effective, particularly in the Type IIb autoimmune subtype, with response rates of 60 to 70 percent in refractory cases. Monitoring of renal function, blood pressure, and lipids is required, with duration limited to less than 2 years. Other options with more limited evidence include montelukast as an add-on (with modest benefit, possibly greater in NSAID-exacerbated urticaria), dapsone at 50 to 150 mg daily for urticarial vasculitis or neutrophil-predominant CSU, colchicine for urticarial vasculitis, and hydroxychloroquine for urticarial vasculitis or autoimmune-associated disease. Investigational agents include ligelizumab (a higher-affinity anti-IgE antibody, though phase 3 trials did not demonstrate superiority over omalizumab) and Bruton's tyrosine kinase (BTK) inhibitors such as remibrutinib and fenebrutinib, which have shown promising results in phase 3 REMIX trials and may represent the next standard-of-care therapy for refractory CSU.

## Chronic Inducible Urticaria (CIndU)

### Subtypes and Provocation Testing

Symptomatic dermographism is the most common chronic inducible urticaria, in which wheals develop from stroking or scratching the skin. Diagnosis is confirmed by applying standardized pressure with a dermographometer or tongue depressor and reading the result at 10 minutes.

Cold urticaria produces wheals upon exposure to cold air, water, or objects. The diagnostic test involves application of a TempTest device or ice cube (wrapped in a thin bag) to the forearm for 5 minutes, with the result read 10 minutes after rewarming. A critical safety concern is that full-body cold exposure, such as swimming in cold water, carries a risk of anaphylaxis. Secondary causes, including cryoglobulinemia and cryopyrinopathies (familial cold autoinflammatory syndrome), should be excluded.

Delayed pressure urticaria produces deep swelling 4 to 6 hours after sustained pressure. Testing involves applying a 7 kg weight to the thigh or shoulder for 15 minutes with reading at 6 hours. This subtype responds poorly to antihistamines and may benefit from dapsone or omalizumab.

Solar urticaria develops within minutes of exposure to ultraviolet or visible light and is diagnosed through phototesting with graded exposures to UVA, UVB, and visible light. Cholinergic urticaria produces characteristic small (2 to 4 mm), monomorphic wheals triggered by a rise in core body temperature from exercise, hot baths, or emotional stress. Provocation testing involves exercise or hot bath challenge. This entity must be distinguished from exercise-induced anaphylaxis, which produces larger wheals and systemic symptoms.

| CIndU Subtype | Trigger | Diagnostic Test | Key Features |
|---|---|---|---|
| Symptomatic dermographism | Stroking/scratching | Dermographometer, read at 10 min | Most common CIndU |
| Cold urticaria | Cold air, water, objects | TempTest or ice cube 5 min, read at 10 min after rewarming | Risk of anaphylaxis with full-body cold exposure |
| Delayed pressure urticaria | Sustained pressure | 7 kg weight on thigh/shoulder for 15 min, read at 6 hr | Poor antihistamine response; may respond to dapsone or omalizumab |
| Solar urticaria | UV or visible light | Phototesting with graded UVA, UVB, visible light | Onset within minutes of exposure |
| Cholinergic urticaria | Rise in core body temperature | Exercise or hot bath challenge | Small 2-4 mm monomorphic wheals; distinguish from exercise-induced anaphylaxis |
| Vibratory urticaria | Vibratory stimuli | Vibratory challenge | Familial cases: ADGRE2 (EMR2) mutation |
| Aquagenic urticaria | Water contact (any temperature) | Water application test | Rare |

Vibratory urticaria and angioedema is triggered by vibratory stimuli, with familial cases associated with gain-of-function mutations in the ADGRE2 (EMR2) gene. Aquagenic urticaria, a rare condition, produces small wheals from water contact regardless of temperature.

## Angioedema Without Wheals

When angioedema occurs without accompanying urticaria, it is essential to distinguish histamine-mediated from bradykinin-mediated mechanisms, as the treatment approaches are fundamentally different. Histamine-mediated angioedema responds to antihistamines and epinephrine, may accompany urticaria, and is characteristically pruritic. Bradykinin-mediated angioedema does not respond to antihistamines or epinephrine, is not pruritic but rather painful, and does not present with urticaria.

| Feature | Histamine-Mediated Angioedema | Bradykinin-Mediated Angioedema |
|---|---|---|
| Pruritus | Present | Absent (pain/pressure instead) |
| Urticaria | Often accompanies | Absent |
| Onset | Rapid | Slower |
| Response to antihistamines | Yes | No |
| Response to epinephrine | Yes | No |
| Response to corticosteroids | Partial | No |
| Causes | Allergic reactions, mast cell activation | HAE, ACE inhibitor, acquired C1-INH deficiency |

ACE inhibitor-induced angioedema affects 0.1 to 0.7 percent of ACE inhibitor users, with higher risk in Black patients. The mechanism involves ACE-mediated degradation of bradykinin; when ACE is inhibited, bradykinin accumulates and causes vasodilation and increased vascular permeability. A critically important clinical feature is that onset may occur weeks to years after initiating stable ACE inhibitor therapy. Resolution typically occurs within 24 to 72 hours of ACE inhibitor discontinuation, and the medication must be permanently stopped. The risk of angioedema with angiotensin receptor blockers is approximately 2 to 8 percent. Hereditary angioedema is discussed in a separate dedicated lecture.

<image>A comparison table-style illustration distinguishing histamine-mediated from bradykinin-mediated angioedema. Two columns with clinical images. Left column (Histamine-mediated): shows facial angioedema with concurrent urticarial wheals, labeled features include pruritus, rapid onset, often accompanies urticaria, responds to epinephrine and antihistamines, associated with mast cell activation (elevated tryptase). Right column (Bradykinin-mediated): shows lip and tongue angioedema without wheals, labeled features include pain/pressure (not itch), slower onset, NO wheals, does NOT respond to epinephrine/antihistamines/steroids, associated with C4 consumption (HAE) or ACEi use. Bottom section: laboratory evaluation algorithm - measure C4 level; if low, proceed to C1-INH level and function; if normal, consider ACEi-related, idiopathic, or HAE with normal C1-INH. Decision tree leads to specific diagnoses (HAE Type I, II, III, acquired C1-INH deficiency).</image>

## Urticarial Vasculitis

Urticarial vasculitis is distinguished from ordinary urticaria by several key features: individual wheals persist beyond 24 hours, the quality of discomfort is painful or burning rather than pruritic, and lesions leave residual purpura or hyperpigmentation upon resolution. Histologic examination reveals leukocytoclastic vasculitis with neutrophilic infiltrate, fibrinoid necrosis of vessel walls, and nuclear dust (karyorrhexis).

Normocomplementemic urticarial vasculitis (NUV) is generally milder and confined to the skin. Hypocomplementemic urticarial vasculitis syndrome (HUVS) is a systemic disease characterized by depressed C1q, C3, and C4 levels, anti-C1q autoantibodies, and associated features including glomerulonephritis, uveitis, arthritis, chronic obstructive pulmonary disease, and angioedema. HUVS may overlap with systemic lupus erythematosus. Treatment options include dapsone, colchicine, and hydroxychloroquine for milder disease, with corticosteroids, mycophenolate mofetil, and rituximab reserved for severe cases.

## Key Clinical Pearls
- CSU is NOT caused by food allergy; do not pursue extensive allergen testing panels
- Individual wheals in urticaria last <24 hours; wheals >24 hours or residual bruising should prompt biopsy for urticarial vasculitis
- Updosing second-generation antihistamines to 4x standard dose is guideline-recommended before adding omalizumab
- Omalizumab for CSU uses fixed dosing (150 or 300 mg q4 weeks) not based on IgE/weight; onset may take weeks to months
- Cold urticaria carries risk of anaphylaxis with full-body cold exposure (swimming); prescribe epinephrine auto-injector
- Angioedema without urticaria that does not respond to antihistamines/epinephrine should prompt evaluation for bradykinin-mediated angioedema (HAE or ACEi-related)
- ACEi angioedema can occur years after initiating therapy; stop ACEi permanently; risk with ARBs is ~2-8%
- Chronic urticaria is NOT a contraindication to immunization or general anesthesia

## References
1. Zuberbier T, et al. The international EAACI/GA2LEN/EuroGuiDerm/APAAACI guideline for the definition, classification, diagnosis, and management of urticaria. *Allergy*. 2022;77(3):734-766.
2. Maurer M, et al. Omalizumab for the treatment of chronic idiopathic or spontaneous urticaria (ASTERIA I). *N Engl J Med*. 2013;368(10):924-935.
3. Kolkhir P, et al. Urticaria. *Nat Rev Dis Primers*. 2022;8(1):61.
4. Bernstein JA, et al. The diagnosis and management of acute and chronic urticaria: 2014 update. *J Allergy Clin Immunol*. 2014;133(5):1270-1277.
5. Magerl M, et al. The definition, diagnostic testing, and management of chronic inducible urticarias. *J Allergy Clin Immunol*. 2016;138(1):56-66.