Urticaria / angioedema

Meet the patient

A 34-year-old woman has daily itchy wheals for three months; each lesion fades within hours, her sleep is wrecked, and a routine "allergy panel" her GP ordered is negative. This is chronic spontaneous urticaria — not an allergy, and the panel was wasted money.[2][3]

Now picture the patient who scares you: a 24-year-old with recurrent lip and tongue swelling, no wheals, no itch, and a father who "choked to death" in his twenties. Adrenaline, antihistamines, and steroids will do nothing here — this is hereditary angioedema, bradykinin-driven, and the drug that saves his airway is C1-INH concentrate or icatibant, not the anaphylaxis bundle. Hold that contrast and the whole topic is structured.[18][20]

The dichotomy that decides everything

Angioedema is either histamine-driven or bradykinin-driven, and the wrong treatment is not just useless — it delays the one that works. Histaminergic angioedema accompanies wheals and itch, comes on in minutes, and responds to antihistamines, corticosteroids, and adrenaline. Bradykinin-mediated angioedema is isolated (no wheals, no itch), slower, lasts days, and is blind to all three.[18][19][20]

[1]

The classic trap: reaching for adrenaline, antihistamines, and steroids in a bradykinin-mediated attack. They will not work, and every minute spent on them delays the C1-INH concentrate or icatibant that will. The wheal history is the single most reliable discriminator at the bedside.[18][19]

Definition and classification — the six-week gate

A wheal has three features: a central swelling with a reflex erythema, an itching or burning sensation, and a fleeting nature — the skin returns to normal usually within 1 to 24 hours. Angioedema is sudden swelling of the lower dermis and subcutis, more painful than itchy, pale rather than red, resolving over hours to (occasionally) 72 hours.[3]

The six-week threshold separates acute from chronic. Acute urticaria (under six weeks) is often infection-, drug-, or food-triggered and self-limiting. Chronic urticaria (six weeks or longer) splits into chronic spontaneous urticaria (CSU) — wheals or angioedema with no identifiable external trigger — and inducible urticaria, elicited by a specific physical stimulus and confirmed by provocation testing.[1][3]

The inducible urticarias are heterogeneous: symptomatic dermographism (shearing force — the commonest), cold urticaria (carry a drowning risk on whole-body cold immersion), delayed pressure urticaria (deep painful swelling 4 to 8 hours after pressure, antihistamine-resistant), solar, cholinergic, heat, vibratory, aquagenic, and contact urticaria.[3]

How common, and who

The lifetime prevalence of any urticaria is about 20 per cent, and chronic urticaria affects about 1 per cent of the population at any time, with CSU accounting for around two-thirds of chronic cases. A global meta-analysis reports a CSU point prevalence of about 0.7 per cent, a female predominance of about 2 to 1, and peak onset between 20 and 40 years. Mean duration is 1 to 5 years, but 10 to 15 per cent persist beyond 5 years.[4][2]

The mast-cell axis — and why CSU is not a pure histamine disease

Wheal and flare reflect activation of skin mast cells around post-capillary venules, with release of histamine, platelet-activating factor, prostaglandin D2, leukotrienes, and cytokines. Histamine on H1 receptors drives itch and vasodilatation; on H2 receptors, permeability. But the modern framework insists CSU is not a pure histamine disease — co-existent kallikrein-kinin axis activation, basophil dysfunction, and a Th1 or Th17 infiltrate all contribute.[5][8]

A substantial fraction of CSU is autoimmune. Functional IgG autoantibodies against the high-affinity IgE receptor Fc-epsilon-RI-alpha (or against IgE itself) cross-link receptor-bound IgE on mast cells and basophils, triggering degranulation. About 30 to 50 per cent of CSU patients carry this autoimmune subset, linked to thyroid autoimmunity, a more prolonged course, a higher disease burden, and a preferential response to immunomodulatory therapy. The autologous serum skin test screens for it; biomarker work (total IgE, CRP, D-dimer, basophil activation markers) continues to refine identification.[6][7][9]

Co-factors that worsen CSU: aspirin and other NSAIDs in 20 to 40 per cent (via cyclo-oxygenase-1 inhibition shifting arachidonic acid toward leukotrienes), Helicobacter pylori, streptococcal and viral hepatitis infection, stress, hormonal factors, alcohol, and opiates. H. pylori eradication produces remission in a subset of infected patients.[3][8]

What you see at the bedside — and the vasculitis trap

In CSU, wheals occur daily or near-daily, appear anywhere, are intensely pruritic, and each lesion resolves within 24 hours. Nocturnal worsening and sleep disturbance are typical. Angioedema accompanies CSU in about 40 per cent — eyelids, lips, tongue, oropharynx, genitals, extremities; laryngeal involvement is an airway emergency. Constitutional symptoms (fever, weight loss, arthralgia) are not features of uncomplicated CSU, and their presence should prompt a search for urticarial vasculitis or a systemic process.[2][3]

[3]

Urticarial vasculitis is the trap to exclude. Suspect it when individual lesions persist beyond 24 hours (often 24 to 72), are painful or burning rather than itchy, leave residual bruising or hyperpigmentation, and come with systemic features — skin biopsy confirms a leukocytoclastic small-vessel vasculitis. The broader differential includes autoinflammatory syndromes (cryopyrin-associated periodic syndromes, Schnitzler syndrome with monoclonal IgM), serum sickness, mastocytosis, drug eruptions, erythema multiforme, and the urticarial pre-bullous phase of bullous pemphigoid.[2]

The EAACI ladder — up-dose, then omalizumab, then ciclosporin

The international guideline endorses a four-step algorithm, and steps 2 and 3 are the two every candidate must reproduce.[3]

[1]

Step 1 — a second-generation H1-antihistamine at standard dose. Bilastine, cetirizine, levocetirizine, desloratadine, fexofenadine, and loratadine are preferred over first-generation agents (which impair cognition, are anticholinergic, and wreck sleep architecture) and have established paediatric safety.[10]

Step 2 — up-dose to four-fold. In patients uncontrolled on the standard dose, increase the second-generation H1-antihistamine to two, then three, then four times the standard dose before escalating. Benefit is seen in a meaningful proportion, with an acceptable safety profile — and this is the single most frequent exam point on CSU management.[1]

Step 3 — add omalizumab. For patients refractory to up-dosed antihistamines, omalizumab (anti-IgE), 300 mg subcutaneously every 4 weeks, is the first add-on. The pivotal trials — ASTERIA II (Maurer, NEJM 2013), ASTERIA I (Saini), and GLACIAL (Casale) — showed dose-dependent increases in well-controlled weeks, with onset usually within 1 to 2 weeks and roughly two-thirds of treated patients achieving a complete response.[11][12][13][14]

Step 4 — ciclosporin. In omalizumab non-responders or where it is unavailable, ciclosporin 2.5 to 4 mg/kg/day, cautiously titrated, with blood-pressure and renal-function monitoring, because of nephrotoxicity and hypertension. Mycophenolate, tacrolimus, and short low-dose corticosteroid tapers are off-label options in refractory disease.[1]

The pipeline — BTK, IL-4 receptor alpha, and KIT

Dupilumab (anti-IL-4 receptor alpha) showed significant reductions in itch and hive scores at 24 weeks in the LIBERTY-CSU CUPID phase 3 trials and is now approved for CSU in several jurisdictions, including children.[15]

Remibrutinib, an oral covalent Bruton tyrosine kinase inhibitor, produced rapid and substantial UAS7 reductions in a 2025 phase 3 trial (Metz, NEJM 2025), addressing the mast-cell and basophil signalling axis upstream of histamine.[16]

Barzolvolimab, an anti-KIT monoclonal antibody that depletes mast cells, shows dose-dependent improvement, with the notable on-treatment effect of transient hair colour change (grey repigmentation) from mast-cell depletion at the hair bulb.[17]

Inducible urticaria specifics: dermographism, cold, cholinergic, and solar urticarias are managed with up-dosed second-generation H1-antihistamines; omalizumab is effective for several forms. Warn cold-urticaria patients of the drowning risk with whole-body cold immersion; delayed pressure urticaria is notoriously antihistamine-resistant and may need NSAID avoidance and short corticosteroid courses.[3]

Hereditary angioedema — the bradykinin disease that kills

HAE is an autosomal dominant disorder of C1-inhibitor (SERPING1), prevalence about 1 in 50,000. C1-INH normally inhibits activated factor XII, plasma kallikrein, and complement C1r and C1s; its absence permits uncontrolled bradykinin generation via the contact system, producing non-pitting, non-pruritic swelling of subcutaneous and submucosal tissues. The swelling is not histamine-mediated and does not respond to adrenaline, antihistamines, or corticosteroids.[20][21]

Classification: HAE type I (about 85 per cent) — low antigenic and functional C1-INH. HAE type II (about 15 per cent) — normal or raised antigenic C1-INH but dysfunctional protein. HAE with normal C1-INH — mutations in F12, plasminogen, angiopoietin-1, or kininogen; oestrogen-sensitive, predominantly women. Acquired angioedema (AAE) — adult-onset, no family history, low C4 and low C1q, usually a B-cell lymphoproliferative disorder or anti-C1-INH autoantibody.[18][20]

Attacks are episodic, last 2 to 5 days untreated, and hit the skin, the abdomen (visceral oedema producing severe pain, nausea, vomiting, and diarrhoea that mimics a surgical abdomen), and the upper airway. Laryngeal attacks are the principal cause of death — historical mortality from laryngeal attacks approached one-third of untreated patients. Triggers include trauma (notably dental procedures), stress, infection, oestrogen-containing contraceptives, pregnancy, and ACE inhibitors.[23]

[1]

The HAE on-demand and prophylaxis ladder

Every HAE patient must carry at least two doses of an approved on-demand agent and use it at the earliest symptom — treatment within the first hour shortens the attack and reduces progression to laryngeal involvement.[21][22]

Long-term prophylaxis is indicated for frequent or severe attacks, prior laryngeal attacks, major quality-of-life impairment, or poor emergency access. The modern agents target plasma kallikrein or factor XIIa:[21][22]

[24] [25] [26]

Short-term prophylaxis before dental work, endoscopy, or intubation: plasma-derived C1-INH concentrate 1000 units IV one to six hours before the procedure (preferred), attenuated androgens, or tranexamic acid (the weaker option, useful in pregnancy).[21]

HAE in children and pregnancy demands age-appropriate on-demand dosing, school emergency plans, and avoidance of attenuated androgens (growth effects in children, teratogenicity in pregnancy). A C1-INH concentrate-based strategy is preferred in pregnancy; ACE inhibitors must be avoided.[28][22]

[1]

ACE-inhibitor angioedema — the iatrogenic bradykinin disease

ACE degrades bradykinin, so its inhibition produces excess bradykinin. ACE-inhibitor angioedema occurs in 0.1 to 0.7 per cent of patients, can first appear years after initiation, and disproportionately affects Black patients, women, and smokers. It presents as isolated swelling of the lips, tongue, face, or upper airway without urticaria. Management is stop the ACE inhibitor permanently (never rechallenge), supportive airway care (the priority — early intubation if the airway is threatened), and consideration of icatibant, C1-INH concentrate, or ecallantide in severe or refractory cases, because conventional anaphylaxis therapy is ineffective. Switch to an ARB, not another ACE inhibitor.[27][19]

Acquired angioedema (AAE) presents in adulthood without family history, with low C4 and low C1q, often an underlying B-cell lymphoproliferative disorder or anti-C1-INH autoantibody; management combines treatment of the associated condition with C1-INH concentrate or bradykinin-targeted agents for acute attacks.[18][19]

Anaphylaxis and the airway — when histamine meets the airway

Acute generalised urticaria with airway compromise, hypotension, persistent gastrointestinal symptoms, or wheeze meets criteria for anaphylaxis and needs immediate intramuscular adrenaline into the anterolateral thigh, repeatable every 5 to 15 minutes, airway support, high-flow oxygen, intravenous fluids, supine positioning, and observation. Adjuncts (H1 and H2 antihistamines, corticosteroids) treat cutaneous symptoms but do not substitute for adrenaline. Angioedema with stridor, dysphonia, or drooling is an airway emergency regardless of mechanism; in HAE the on-target agent (C1-INH concentrate or icatibant) must be given alongside airway protection.[23][21]

Investigations — focused, not a fishing expedition

The diagnosis of urticaria is clinical. Routine allergy panels are not indicated in CSU — over-investigation is common and the yield is low. The EAACI guideline recommends a focused, stepwise evaluation.[3]

All patients get a detailed history (onset, frequency, duration, triggers, co-factors, drugs, diet, infection, quality of life), examination, and a differential blood count with CRP; for CSU, add an ESR or CRP and consider C4 to screen for HAE.[1]

Screen for HAE whenever angioedema occurs without wheals: complement C4 (low in HAE types I and II and in AAE), C1-INH antigen and function (function is the most reliable single test), and C1q (low in acquired disease). First-degree relatives should be screened because of autosomal dominant inheritance with incomplete penetrance.[20][21][22]

Directed tests only for suspected inducible urticaria (provocation testing — dermographometer, ice cube, phototesting, pressure weights, aquagenic challenge, exercise). Extended work-up reserved for atypical features: thyroid autoantibodies and function, Helicobacter pylori, stool ova and parasites, tryptase (to screen for clonal mast-cell disorder and stratify anaphylaxis risk), hepatitis and HIV if risk factors, and skin biopsy for suspected urticarial vasculitis.[1]

Ward-round test

A patient with recurrent lip and tongue swelling has no wheals and no itch, and a low C4. What is the diagnosis, and which acute treatment will — and will not — work?

Hereditary angioedema (HAE) — bradykinin-mediated, autosomal dominant C1-INH deficiency. The angioedema occurs without urticaria or itch, which is the bedside signature that separates it from histaminergic angioedema. Adrenaline, antihistamines, and corticosteroids will NOT work — this is the classic trap. The on-demand agents that do work are C1-INH concentrate (Berinert 20 units/kg IV), icatibant (30 mg SC), or ecallantide (30 mg SC). Confirm with C1-INH antigen and function (function is the most reliable test), and start long-term prophylaxis with lanadelumab or berotralstat if attacks are frequent. Screen first-degree relatives.[20][21]

A patient with CSU is uncontrolled on a standard-dose second-generation antihistamine. What are the next two steps in the EAACI algorithm, with doses?

Step 2 — up-dose the antihistamine to four-fold (two, then three, then four times the standard dose) before any add-on. Step 3 — add omalizumab 300 mg subcutaneously every 4 weeks, the first add-on, established by the ASTERIA I and II and GLACIAL trials. Onset is within 1 to 2 weeks and about two-thirds achieve a complete response. Step 4, for omalizumab non-responders, is ciclosporin 2.5 to 4 mg/kg/day with blood-pressure and renal monitoring. Do not jump to ciclosporin or oral steroids without first exhausting the up-dose and omalizumab steps.[3][11]

A 60-year-old on lisinopril for five years presents with tongue and floor-of-mouth swelling, no wheals, and stridor. What do you do in the first 15 minutes?

ACE-inhibitor angioedema — a bradykinin-mediated airway emergency. Secure the airway first (early elective intubation by an experienced operator, not an emergency tracheostomy if avoidable). Stop the lisinopril permanently and never rechallenge; switch later to an ARB. Adrenaline, antihistamines, and corticosteroids are ineffective — give icatibant 30 mg SC, C1-INH concentrate, or ecallantide in severe or refractory cases. ACE-inhibitor angioedema can first appear years after initiation and may be fatal; Black patients, women, and smokers are at higher risk.[27][19]

References

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