• Epidermis: outermost avascular layer; barrier function
• Dermis: where the action happens in urticaria — contains blood vessels, nerve endings, and importantly, mast cells
  • Superficial (papillary) dermis: urticaria occurs here — mast cell degranulation → histamine release → vasodilation and increased capillary permeability → dermal oedema = the wheal
  • Deep dermis / subcutaneous tissue: when the same process extends deeper → angioedema (swelling of subcutaneous/submucosal tissue, classically lips, eyelids, tongue, genitalia, hands/feet)

Pathophysiology: mast cell degranulation with histamine release → temporary increased capillary permeability → localized dermal oedema ^[2]

Mast cells reside in connective tissues, especially around blood vessels, nerves, and at mucosal surfaces. They contain preformed granules packed with:

• Histamine (the dominant mediator in urticaria)
• Tryptase, chymase
• Heparin
• TNF-α

When activated, mast cells also generate de novo mediators:

• Prostaglandin D₂ (PGD₂)
• Leukotrienes (LTC₄, LTD₄, LTE₄)
• Platelet-activating factor (PAF)
• Cytokines (IL-4, IL-5, IL-13 → Th2 skewing)

This is the critical receptor on the mast cell surface:

• When an allergen cross-links two IgE molecules bound to FcεRI → mast cell degranulation (classical Type I hypersensitivity)
• In autoimmune CSU, the patient produces IgG autoantibodies against FcεRI (anti-FcεRIα) or against IgE itself → these autoantibodies cross-link and activate the mast cell directly

Spontaneous or autoimmune urticaria and angioedema (CSU) is driven by anti-FcεRIα antibody (on mast cells) ^[1]

The current EAACI/GA²LEN/EDF/WAO 2022 international guidelines classify chronic urticaria into:

These urticarias have a specific, reproducible physical or environmental trigger. Multiple types may coexist.

Inducible urticaria and angioedema = identifiable trigger(s) ^[1]

The wheal (hive) in urticaria is produced by a three-step process:

1. Mast cell activation (by any of the above mechanisms)
2. Mediator release:
   • Histamine → binds H₁ receptors on endothelial cells → vasodilation + increased vascular permeability → plasma extravasation into the dermis → oedema (= the wheal)
   • Histamine → binds H₁ receptors on sensory nerve endings → itch (pruritus)
   • Histamine → binds H₁ receptors on postcapillary venules → axon reflex → flare (erythema surrounding the wheal)
3. Resolution: within 24 hours, the oedema fluid is reabsorbed by lymphatics and the wheal disappears without scarring or residual pigmentation

In angioedema: the same process occurs but in the deeper dermis and subcutaneous tissue, producing diffuse swelling rather than discrete wheals. Angioedema is less itchy but more often painful or have a burning sensation, and resolves more slowly (up to 72 hours).

Histaminergic urticaria pathway: Mast cell degranulation → histamine → H₁ receptor activation → vasodilation + ↑capillary permeability → dermal oedema (wheal) ^[1][2]

Not all angioedema is histaminergic! This distinction is critical for management:

Hereditary angioedema: Type I (85%, low C1-INH level) and Type II (15%, normal level but low function) — both due to SERPING1 mutation → inability to inhibit kallikrein → excess bradykinin → angioedema ^[6]

CSU can be further subdivided:

• Type I autoimmune CSU: IgE against self-antigens (autoallergic)
• Type IIb autoimmune CSU: IgG against FcεRIα or IgE (autoimmune)
• Non-autoimmune CSU: idiopathic, infection-related, other

This newer classification is clinically relevant because Type IIb autoimmune CSU tends to be more severe, more refractory to standard antihistamines, and responds better to omalizumab (anti-IgE monoclonal antibody) ^[7].

When evaluating a patient with chronic urticaria, systematically ask:

1. Onset and duration: When did it start? How long has it been going on? (< 6 weeks vs ≥ 6 weeks)
2. Individual lesion duration: Does each wheal last < 24 hours? (crucial — if > 24h, consider urticarial vasculitis)
3. Residual marks: Any bruising, pigmentation, or scarring after wheals resolve? (if yes → urticarial vasculitis)
4. Pattern: Spontaneous or triggered? What triggers? (heat, cold, pressure, exercise, stress, water, sun)
5. Angioedema: Any deep swelling of lips, eyes, tongue, hands, feet? Any throat tightness or breathing difficulty?
6. Systemic symptoms: Fever, joint pain, weight loss? (if present → think urticarial vasculitis, serum sickness, SLE)
7. Drug history: NSAIDs, aspirin, ACE inhibitors, antibiotics, opioids, supplements, TCM
8. Infection history: Recent URTI, GI symptoms (H. pylori), dental issues
9. Personal/family history of atopy: Asthma, eczema, allergic rhinitis, food allergy
10. Personal/family history of autoimmune disease: Thyroid disease, SLE, vitiligo, type 1 DM
11. Family history of angioedema without urticaria: Think hereditary angioedema (C1-INH deficiency)
12. Impact on QoL: Sleep, work, mood, social functioning
13. Prior treatments and response: Antihistamines? What dose? Response?

Clinical differentiation between Type I (immediate) and Type IV (delayed) allergic reactions is critical — ask about timing (Type I: within 1 hour; Type IV: beyond hours to days) and type/nature of symptoms ^[9]

Why the difference? In urticaria, the vessel wall remains intact — histamine simply opens inter-endothelial gaps transiently. In urticarial vasculitis, there is actual immune-complex deposition in postcapillary venule walls (Type III hypersensitivity) → complement activation → neutrophil recruitment → vessel wall destruction → RBC leak → purpura. Because the vessel is structurally damaged, the lesion takes longer to resolve and leaves a mark.

Urticaria > 24 hours → DDx: urticarial vasculitis and pre-bullous bullous pemphigoid ^[3]

• Who: elderly patients (typically > 70 years)
• What: pre-bullous urticarial papules that look very non-specific initially — can be mistaken for eczema or urticaria ^[3]
• Must recognize early signs of bullous pemphigoid → appears eczematous beforehand, very non-specific and can be missed ^[3]
• Pre-bullous urticarial papules → which is why it is so important that you are alert once patient reports urticaria that does not resolve within 24 hours ^[3]
• Eventually evolves into tense blisters on an erythematous/urticarial base
• Why it mimics urticaria: the autoantibodies (anti-BP180, anti-BP230) against the basement membrane zone initially cause inflammatory oedema before full subepidermal blister formation
• Key distinguishing features:
  • Individual lesions persist > 24h
  • Elderly patient
  • Lesions may evolve into vesicles/bullae
  • Anti-skin antibody positive ^[3]
  • Biopsy: subepidermal split with eosinophilic infiltrate; direct immunofluorescence (DIF) shows linear IgG and C3 at the basement membrane zone

• Target lesions: concentric rings with central dusky area (unlike the homogeneous wheal of urticaria)
• Individual lesions are fixed (stay in the same location for days) — urticarial wheals are migratory
• Often associated with HSV infection (most common trigger) or Mycoplasma pneumoniae ^[10]
• Lesions may be slightly tender rather than purely pruritic
• Why it can mimic urticaria: early or atypical EM lesions may look like annular wheals before the classic target morphology develops

• Fixed brown-red macules/papules that urticate on rubbing (Darier's sign = wheal and flare at site of rubbing a lesion)
• Unlike urticaria, the lesions are persistent and always in the same location — it is the background lesion that is permanent, and stroking just makes it flare transiently
• Pathophysiology: abnormal clonal proliferation of mast cells in the skin → excessive mast cell numbers → easy degranulation
• Why it can mimic urticaria: the urticarial flare on top of lesions looks like wheals; systemic symptoms (flushing, GI) overlap
• Serum tryptase often chronically elevated (unlike CSU where tryptase is usually normal between flares)

• Can present with urticarial plaques in the acute phase
• Key difference: distribution matches the contactant pattern (e.g., watch strap, nickel in jewellery, rubber gloves) and lesions have epidermal changes (vesicles, scaling, crusting) that are absent in urticaria
• Mechanism: Type IV (delayed) hypersensitivity, not mast cell-mediated

• Type I (IgE-mediated, immediate): urticaria ± angioedema ± anaphylaxis — within minutes to hours of drug exposure ^[10][11]
• Type IV (T-cell mediated, delayed): maculopapular eruption (the most common drug eruption morphology) — days to weeks after drug exposure ^[10]
• The maculopapular eruption of a drug reaction can look urticarial but lesions are fixed, not transient, and often have epidermal change (fine scale)
• DRESS, SJS/TEN, AGEP — these are severe cutaneous adverse reactions (SCAR) that may begin with urticarial features but rapidly evolve ^[10]

• Subacute eczema can sometimes look urticarial with oedematous pink plaques
• Key difference: epidermal changes (scaling, vesicles, lichenification) are present; lesions are not transient
• Common in elderly patients — overlap with pre-bullous BP should always be considered

• Cryopyrin-associated periodic syndrome (CAPS): recurrent fever and urticaria ^[12]
• These are not mast-cell mediated — they are driven by inflammasome hyperactivation (NLRP3 gain-of-function) → excess IL-1β
• Urticarial rash is typically non-pruritic (neutrophilic, not histaminergic), associated with fever, and present from infancy
• Does NOT respond to antihistamines → responds to IL-1 blockade (anakinra, canakinumab)

Each type of CIndU has a specific provocation test:

The diagnosis of chronic urticaria requires all of the following:

Chronic urticaria: lasts > 6 weeks; rarely IgE-dependent; mostly 'idiopathic' ^[14]

Once chronic urticaria is confirmed, it must be subclassified:

These can coexist — a patient may have CSU with concomitant dermographism, for example. Each type should be individually assessed.

Disease activity in CSU is measured using standardised scoring systems. These are important for clinical trials, treatment escalation decisions, and monitoring:

UAS7 interpretation:

• 0: urticaria-free
• 1–6: well-controlled
• 7–15: mild
• 16–27: moderate
• 28–42: severe

The 2022 international guidelines recommend minimal routine baseline tests for CSU. The rationale: most CSU is idiopathic/autoimmune, and blanket testing for infections, autoimmune diseases, and allergies in every patient is not cost-effective.

These two tests serve as a safety net to catch occult systemic disease. If they are normal and the history is straightforward, further testing may not be needed.

First-line treatment = 2nd-generation antihistamine ^[7][15]

Why antihistamines work: Histamine is the dominant mediator released by mast cells in urticaria. It binds to H₁ receptors on endothelial cells (→ vasodilation, ↑permeability → wheal), sensory nerve endings (→ itch), and smooth muscle. H₁-antihistamines are inverse agonists — they stabilise the H₁ receptor in its inactive conformation, preventing histamine from activating it.

Avoid mixing different types of H1-antihistamines ^[15]

Why not mix different antihistamines? There is no pharmacological rationale for combining two different sgAH at standard doses — they all target the same H₁ receptor. Instead of mixing, the guideline approach is to updose a single agent (Step 2). Mixing creates confusion in monitoring response and adds no proven benefit.

Onset: Clinical effect within 1–2 hours; steady-state plasma levels within 3–5 days of regular dosing.

When to assess response: 2–4 weeks of regular daily use at each step before deciding to escalate ^[15].

Up to 4 tablets ^[7] / Doses of up to fourfold the standard dose may be used for CSU ^[15]

Why does updosing work? At standard doses, H₁ receptor occupancy is approximately 70–80%. Increasing to 4× dose pushes receptor occupancy closer to 95–100%. Additionally, mast cells release very large amounts of histamine in CSU — standard doses may simply be insufficient to compete with such high local histamine concentrations.

Safety of updosing: Multiple RCTs and meta-analyses confirm that sgAH at up to 4× dose remain safe and well-tolerated. Sedation may increase slightly with cetirizine/levocetirizine at high doses, but is generally manageable. Fexofenadine and bilastine remain essentially non-sedating even at 4× dose.

Key counselling point: Patients often take antihistamines PRN (as-needed). In chronic urticaria, regular daily dosing is essential — the goal is to maintain constant H₁ receptor blockade, not to chase symptoms after they appear.

Biologics also exist for chronic urticaria ^[7] / Anti-IgE monoclonal antibodies (omalizumab) ^[15]

What is omalizumab? Omalizumab (Xolair®) is a recombinant humanised monoclonal IgG₁ antibody that binds to the Cε3 domain of free IgE — the same region that binds to FcεRI. By binding free IgE, it prevents IgE from attaching to mast cells and basophils.

Break down the name: "o-" = humanised monoclonal antibody; "-mab" = monoclonal antibody; "-lizu-" = immunomodulatory target (IgE).

Why does omalizumab work in CSU?

1. Reduces free IgE → less IgE bound to mast cell FcεRI → mast cells become less "armed" and less easily activated
2. Downregulates FcεRI expression: when less IgE is available to bind FcεRI, mast cells adaptively reduce the number of FcεRI on their surface (receptor density is proportional to IgE levels) → further ↓ mast cell responsiveness
3. In Type I autoimmune CSU (IgE against self-antigens), omalizumab directly removes the pathogenic IgE autoantibodies
4. In Type IIb autoimmune CSU (IgG against FcεRI), the mechanism is less direct — it may work by reducing FcεRI density, making the receptor less available as a target for the autoantibody

Cyclosporin ^[15]

What is ciclosporin? Ciclosporin (also spelled cyclosporine) is a calcineurin inhibitor — it blocks calcineurin, a phosphatase enzyme required for T-cell activation (specifically, it prevents dephosphorylation of NFAT → blocks IL-2 transcription → ↓ T-cell proliferation). But in CSU, its mechanism of action extends beyond T-cells:

• Mast cell stabilisation: ciclosporin directly inhibits mast cell histamine release
• Inhibits basophil histamine release
• Reduces autoantibody-driven mast cell activation (relevant in Type IIb autoimmune CSU)

These are NOT part of the core stepwise algorithm but may be considered in specific scenarios:

The fundamental approach is the same stepwise algorithm (sgAH → updose → omalizumab → ciclosporin), plus trigger avoidance and specific measures:

• Same stepwise algorithm applies
• Angioedema in CSU is histaminergic — responds to the same treatments (sgAH, omalizumab, ciclosporin)
• If angioedema occurs WITHOUT wheals and does NOT respond to antihistamines → re-evaluate for bradykinin-mediated angioedema (ACEi, HAE)

When urticaria is part of an anaphylactic reaction (respiratory/cardiovascular compromise), this becomes an emergency:

IM adrenaline 0.5 mg (1:1000) Q5 min — first and most important treatment. Chlorpheniramine IV. Hydrocortisone IV. Observe at least 24h for second phase reaction. Take blood for mast cell tryptase immediately, 2h after and 24h after ^[2][16]

This is covered in detail in the anaphylaxis section but key points in the CU context:

• Cold urticaria patients can develop anaphylaxis with total-body cold exposure (cold water immersion) — prescribe epinephrine autoinjector
• Exercise-induced urticaria/anaphylaxis — prescribe epinephrine autoinjector; advise exercising with a partner; avoid triggering food before exercise

Angioedema accompanies CSU in approximately 40–50% of patients. It represents the same mast cell → histamine → ↑vascular permeability process but occurring in the deeper dermis and subcutaneous/submucosal tissue, producing diffuse, non-pitting swelling.

While CSU itself does not typically cause anaphylaxis, certain inducible urticaria subtypes carry a genuine anaphylaxis risk:

Although urticaria itself resolves without residual marks, the intense chronic pruritus leads to habitual scratching, which can cause secondary complications:

Studies consistently show that CSU impairs quality of life to a degree comparable to moderate-to-severe ischaemic heart disease. The CU-Q₂oL (Chronic Urticaria Quality of Life) instrument captures multiple domains of impairment: