Introduction

Pathogenesis

‍ ‍Pathogenesis classification

‍ ‍Immunological

‍ ‍ Non-immuological

‍Clinical classification

Acute urticaria

Chronic urticaria

‍ ‍ Idiopathic (chronic spontaneous urticaria)

‍ ‍Inducible

Triggers and associations

Management intro

‍ ‍Investigations

‍ ‍First line Treatment - H1 antihistamines

‍ ‍Montelukast

‍ ‍ H2 antihistamines

‍ ‍Oral steroids

Second line Treatment

‍ ‍Ciclosporin

‍ ‍Omalizumab

‍ ‍Dupilumab

‍ ‍Remibrutinib

‍ ‍Third line treatment

‍ ‍Specific treatment inducible urticarias

‍ ‍

Angioedema without wheals

Urticarial vasculitis

Autoinflammatory syndromes

Contact urticaria

Urticaria (commonly known as 'hives') is one of the most frequently encountered conditions in both general practice and dermatology, affecting up to 20% of the population at some point in their lives. It presents as an intensely pruritic rash characterised by transient weals that typically resolve within 24 hours, often accompanied by a surrounding erythematous flare.

'Wheal and flare' reaction:

• The wheal refers to the raised, pale, oedematous centre — caused by increased vascular permeability allowing fluid to escape into the superficial (papillary) dermis

• The flare is the surrounding erythematous zone — caused by reflex vasodilation

The transient nature of individual lesions (resolving within 24 hours) is a defining clinical feature that helps distinguish urticaria from other dermatoses.

It can be classified in different ways:

Based on pathogenesis:

Immunologic or non-immunologic

Based on length of symptoms:

• Acute urticaria: Symptoms last < 6 weeks

• Chronic urticaria: > 6 weeks of daily or almost daily wheals

• Episodic: Acute intermittent or recurrent

Based on if symptoms and signs are inducible or non-inducible (also known as ‘spontaneous’)

Lifetime prevalence for all types of urticaria is 8 to 24%

Chronic urticaria lifetime prevalence is 1-2%

Angioedema:

Is the result of deeper swelling in the reticular dermis and subcutaneous tissue/submucosa (compared to weals affecting the more superficial papillary dermis)

Common sites are the eyes, lips, oropharynx and genitals but can occur in other sites like the gastrointestinal tract and upper airways

Angioedematous swellings last longer then weals and can persist for a few days

Weals and angioedema often coexist, but either can occur separately

Some forms of urticaria can be associated with systemic symptoms such as:

Lethargy, malaise

Arthralgia

GI disturbance

Wheeze and/or mucosal involvement

Acute urticaria can be a presenting sign of anaphylaxis

The mast cell is a cell that can be found predominantly in skin, submucosa and bowel mucosa

Histamine is produced and stored in the mast cell in granules and is the  most important mediator of urticaria

Urticaria results from mast cell (+/- basophil) degranulation which leads to the release of preformed vasoactive mediators (eg histamine and others such as tryptase)

Get symptoms and signs due to the resulting vasodilation, increased blood flow and increased vascular permeability

Following the initial release of preformed mediators mast cells and other cells (eg eosinophils, neutrophils) make and release secondary mediators like prostaglandins (cyclo-oxygenase enzyme pathway) and leukotrines (lipoxygenase pathway) which are derived from arachidonic acid and further contribute to the symptoms and signs.

Angioedema can involve additional mechanisms such as bradykinin release and as such antihistamines may not be as effective

There are a variety of immunologic, non immunologic, physical and chemical stimuli that can cause urticaria

Angioedema without weals can be seen in conditions where bradykinin is increased

Going into the immunological mechanisms in more detail, this can be related to the adaptive (allergic, autoimmune, immune complex formation) or the innate immune system (activation through toll like receptors or autoinflammatory syndromes)

Allergic (type 1 hypersensitivity reaction)

This is the classic allergic reaction which can cause an acute urticaria

Mast cells express high affinity IgE receptors (FcεRI) on their surface. IgE antibodies sit on these receptors, each with a specific antigen-binding site directed against a particular allergen

When the relevant allergen is encountered, it binds to and bridges two adjacent IgE molecules on the mast cell surface — this is called cross-linking. Cross-linking of IgE triggers activation of the mast cell, leading to degranulation and release of histamine and other preformed mediators, causing urticaria

Types of allergens that can cross-link mast cell-bound IgE include foods, drugs, inhalants, and allergens from insect bites and stings

Autoimmune

Generally chronic spontaneous urticaria is the most likely urticarial condition you will encounter in the Dermatology clinic

Chronic spontaneous urticaria is now increasingly recognised as an autoimmune condition

Over the past 10 years, the understanding of the immunological mechanisms has evolved significantly

CSU can be now classified into two main autoimmune endotypes

Understanding these endotypes is clinically important as they have distinct biomarker profiles and may predict response to different treatments

Type I autoallergic CSU (autoallergy)

This is the commonest endotype

In type I autoallergic urticaria, patients produce auto-IgE antibodies directed against self-antigens

These internal antigens include thyroid peroxidase (TPO), double-stranded DNA (anti-dsDNA) and others

These auto-IgE antibodies bind to the high-affinity IgE receptor (FcεRI) on mast cells and when cross-linked by the relevant autoantigen, the mast cell degranulates and releases histamine, causing wheals

This is called an ‘autoallergic’ condition because the mechanism mirrors a classical type I hypersensitivity reaction, but the allergen is an internal self-antigen rather than an external allergen

Type IIb autoimmune urticaria

In type IIb autoimmune urticaria, patients produce IgG autoantibodies directed against high-affinity IgE receptor (FcεRI) itself or against IgE bound to the receptor. These IgG autoantibodies activate mast cells, basophils and eosinophils, leading to degranulation and histamine release.

This is classified as type IIb (rather than IIa) because the autoantibodies modify the function of the cell (stimulating degranulation) rather than destroying the cell.

While the mast cell is the primary effector cell in all forms of urticaria, in type IIb autoimmune CSU the IgG autoantibodies also activate basophils and eosinophils. This is because basophils, like mast cells, express FcεRI on their surface and can be targeted by the same IgG autoantibodies

The BAT and BHRA are laboratory tests that detect this basophil activation — a positive result supports a type IIb endotype, while a negative result is more in keeping with type I autoallergic disease

It is important to note that in clinical practice many patients fall somewhere between these two endotypes and it may note even be able to classify them into one category

The endotypes represent a spectrum rather than two entirely discrete categories

Immune complex formation and C5a

This pathway is seen in conditions where circulating immune complexes are present, such as hepatitis B and C, EBV infection, SLE, and serum sickness.

Immune complexes activate the complement cascade and this generates C5a (a small protein fragment called anaphyloxin)

C5a binds to C5a receptors on mast cells, causing degranulation and histamine release without any IgE invovlement

Because mast cell activation occurs through C5aR rather than the IgE/FcεRI pathway, these conditions are often resistant to standard urticaria treatment, including high-dose H1 antihistamines and omalizumab

The same mechanism underlies urticarial vasculitis, which represents the more severe end of the spectrum where neutrophil recruitment additionally causes leukocytoclastic damage to vessel walls

Innate immune system:

Toll-like receptors:

Mast cells can also be activated through Toll like receptors

These TLRs recognise pathogen-associated molecular patterns (PAMPs) from microbes which may explain why viral infections and other infections can trigger or exacerbate urticaria.

Auto-inflammatory syndromes:

Get dysregulation of innate immunity leading to persistent uncontrolled inflammation in the absence of an identifiable trigger

Get excessive cytokine production which can lead to urticaria

Urticaria-like rashes can be feature of autoiflammatory syndromes such as:

• Shnitzler syndrome

• Cryoprin-associated periodic syndromes (CAPS)

• Adult-onset Still’s disease

Mast cells can also be activated through non-immunologic mechanisms, where degranulation occurs without involvement of the adaptive or innate immune system

Direct activation through MRGPRX2 receptors

MRGPRX2 is a receptor expressed on mast cells that can be directly activated by a range of drugs and neuropeptides, causing degranulation independently of IgE.

Drugs that activate mast cells through MRGPRX2 include opioids (e.g. codeine, morphine), radiocontrast media, fluoroquinolones and vancomycin.

Substance P, a neuropeptide involved in pain and inflammation signalling, also activates this receptor.

Approximately 10% of patients with urticaria may have gain-of-function mutations in MRGPRX2, leading to more severe disease.

Clinical trials targeting this receptor are currently underway.

Episodes last < 6 weeks

75% of urticaria cases are acute

Angioedema more common in acute cases 

No cause found in over 50% with acute urticaria

Causes include:

Medications- antibiotics, NSAIDs, anticonvulsants, codeine

Infections (particularly viruses in kids) (think hepatitis in adults)

Foods- nuts, shellfish, eggs, cow's milk

Insect bites/stings

In acute urticaria always ask about angioedema.

In particular ask about throat swelling, wheeze/hoarseness, GI side effects.

If have worrying symptoms consider giving subcut adrenaline and send to hospital

If just have urticaria- give non sedating anti-histamines as first line

Urticaria lasting > 6 weeks

This is the commonest type of chronic urticaria where no clear cause is found for it

CSU has a tendency toward spontaneous resolution even without treatment, but the duration varies significantly between individuals

Predictors of longer disease duration:

• Female sex

• Older age at onset

• Angioedema (as a component of CSU)

• Autoimmune markers (especially thyroid autoimmunity)

• Severe baseline activity

• Co-morbid inducible urticaria

• Systemic inflammation

Relapse risk:

Even after resolution, CSU can relapse. A relapse risk of 13-75% has been reported in the literature. The longer the patient has had the condition, the more likely it is to relapse

Associations:

Usually chronic

Weals reproducibly induced by same physical stimulus

Usually appear within few minutes of stimulus and last < 2 hours

(except delayed pressure urticaria which can take 30 min to 12 hours to develop and lasts for a few days)

Some inducible urticarias can present as a spectrum of symptoms from simple pruritus through to severe symptoms

Tests can be confirmed on provocation testing if have this set up

Please note that cold urticaria in particular warrants close attention as it can cause anaphlaxis (eg if person goes cold water swimming or jumps in a plunge pool)

Dermographism (symptomatic): The commonest inducible urticaria. Wheals occur at sites of minor trauma such as scratching or friction.

Provocation test - Stroke the skin with a tongue depressor and wait 10 minutes

Cold contact urticaria: Triggered by exposure to cold water, cold wind or cold surfaces. This is the inducible urticaria most associated with anaphylaxis — particularly with large surface area cold exposure such as swimming in cold water

Patients should carry an adrenaline auto-injector

Consider checking cryoglobulins

Provocation test - place ice cube in sealed plastic bag over forearm for up to 10 mins and allow to rewarm

Cholinergic urticaria: Triggered by a rise in core body temperature, typically through exercise or emotional stress

Characteristically produces small (2–4mm) monomorphic papular wheals rather than the larger wheals seen in other forms of urticaria

Provocation test - exercise patient in warm environment

Delayed pressure urticaria:

Unlike other inducible urticarias, symptoms are delayed — onset 30 minutes to 12 hours after sustained pressure, and swelling can last for days

Occurs at sites of prolonged pressure such as the soles of the feet after walking, the buttocks after sitting, or under tight waistbands

Can be difficult to treat

Solar urticaria:

Triggered by UV exposure (and sometimes visible light)

Consider checking ANA and porphyrins

May benefit from referral to a specialist centre for phototesting to identify the action spectrum, which can guide UV prophylactic phototherapy

Aquagenic urticaria:

Triggered by contact with water at any temperature

Annual FBC as can be associated with PRV, other haem disorders

Provocation test - wet towel for few minutes over most affected area or immerse body part in water (at 37 degrees)

Heat contact urticaria:

Triggered by direct contact with warm objects or hot water. Much rarer than cold contact urticaria.

Vibratory urticaria:

Triggered by vibratory stimuli such as power tools, lawnmowers or motorcycles.

Exercise-induced anaphylaxis: Anaphylaxis triggered by exercise, sometimes only in combination with a co-factor such as food ingestion (particularly wheat/omega-5 gliadin) or NSAIDs

Distinct from cholinergic urticaria in that it can progress to full anaphylaxis

History and exam is key

Assess impact on quality of life (eg DLQI)

Activity of disease should be measured if considering a second line treatment (eg UAS 7 score)

The UAS 7 score ask the patient to score their severity of urticaria based on the number of weals (mild, moderate, severe) and pruritus (mild, moderate, severe) every day over a period of 7 days

Ask about sleep and work/school disturbance

Enquire about symptoms/signs to suggest a vasculitic process:

• Are the lesions persistent rather than self-limiting?

• Are the lesions tender and painful rather than itchy?

• Does the skin show evidence of residual petechiae, purpura or bruising

• Does the patient have any symptoms/signs of underlying disease - fever, malaise, arthralgia, hypertension, blood/protein in urine

Enquire about any potential triggers and associations

Triggers:

• Stress- stressful events may precede urticaria

• Infections:

  • Viral infections

  • Chronic infections- if have found no cause for chronic urticaria enquire about chronic dental infections, reflux (H pylori), recurrent UTIs, sinusitis

• Medications - NSAIDs, Opioids

• Heat, exercise

• Tightly fitting garments

Of note:

Patients often enquire about food as a cause of chronic urticaria but a history enables mediated food allergy to be ruled out pretty quickly

In IgE mediated food allergy symptoms typically occur within 60 minutes of exposure to the offending food rather than coming on overnight or being present first thin in the morning

Also urticaria and angioedema associated with food allergic reactions rarely occur in isolation and you usually have additional symptoms: eg oropharyngeal itch, wheeze, vomiting, abdominal pain

Caveat - There are very rare trickier exceptions:

Food dependent exercise induced anaphylaxis:

• The "Two-Hit" Trigger: An allergic reaction which only occurs when a specific food is consumed and then followed by a secondary cofactor—usually physical exertion, but sometimes alcohol or NSAIDs—within a few hours.

• The Common Culprits: The most frequent offenders are Omega-5 gliadin (a protein in wheat), Lipid Transfer Proteins (tough defensive proteins in plant and fruit skins), and crustacea (shellfish like prawns).

• Why it mimics chronic urticaria: Because the patient usually eats the trigger food frequently without any issue while resting, the hives seem entirely random and inconsistent, hiding the true cause.

Alpha-Gal Syndrome (Red Meat Allergy)

• The Culprit: A unique allergy to a carbohydrate molecule (alpha-gal) found in the meat of mammals (beef, pork, lamb), which is typically acquired after a person is bitten by a tick.

• The Delayed Reaction: Unlike typical protein-based allergies that strike within an hour, the body takes much longer to digest complex carbohydrates, meaning symptoms do not appear until 3 to 8 hours after eating the meat.

• Why it mimics chronic urticaria: Because of the massive time delay, a patient might eat a burger for dinner and wake up at 3:00 AM covered in hives, making it appear as though the urticaria flared up spontaneously overnight.

Acute/episodic spontaneous urticaria:

Skin prick or RAST testing may help confirm type 1 hypersensitivity reaction if suspected but don’t use these tests in chronic urticaria

FBC, CRP/ESR may help identify infective cause

Chronic urticaria:

There are no diagnostic tests for CSU

Could consider:

FBC

ESR/CRP (if elevated could consider urticarial vasculitis, autoinflammatory disease)

IgE

TFT and Thyroid antibodies (association autoimmune thyroid disease)

• 20% patients have thyroid antibodies in CSU vs 6% normal population

Other considerations

If GI symptoms consider TTG antibodies and exclusion of H Pylori

Dentist appointment if any concerns about dentition (? Abscess)

Autoimmune disease (eg coeliac disease): clinical suspicion should remain high but screening in absence of associated features generally not suggested

If concerned for an urticarial vasculitis may consider a biopsy and do a vasculitic screen including complement levels

Biopsy:

Usually don’t require in standard urticaria but may perform in unusual patterns or in cases of suspected vasculitis

Biopsy of an uncomplicated urticarial wheal is often subtle and findings can be quite underwhelming. You may see:

• Dermal oedema — separation of collagen bundles in the upper and mid dermis, often the most striking feature

• A sparse perivascular infiltrate — predominantly lymphocytes, with variable numbers of eosinophils, neutrophils, and occasional basophils

• Mild vascular dilatation — without vessel wall damage

• No leukocytoclasia, no fibrinoid necrosis, no red cell extravasation, and no vasculitis

• The epidermis is normal (helpful in distinguishing from eczematous or other inflammatory dermatoses)

First-Line Treatment & Administration

• Choose a modern 2nd-generation H1-antihistamine: Standard first-line options include fexofenadine, bilastine, cetirizine, levocetirizine, desloratadine, loratadine.

• Dose regularly, not PRN: To effectively prevent wheals and angioedema, these medications must be taken on a regular, daily schedule rather than on an "as-needed" basis.

Escalation & Adjustments

• Uptitrate for poor control: If standard doses do not provide sufficient improvement, increase the dose up to fourfold. Uptitration should be done every 2–4 weeks until symptoms are controlled.

• Switch, don't mix: If a patient has an inadequate response or poor tolerance to their first medication, consider switching them to a different 2nd-generation H1-antihistamine.

  European guidelines advise against combining two different 2nd-generation H1-antihistamines simultaneously due to a lack of supporting evidence.

Maintenance & Tapering

• Maintain the regimen: Encourage patients to continue their daily antihistamines for a set period, even if they have been lesion-free.

• Taper gradually: Once complete symptom control is achieved and sustained, attempt a stepwise dose reduction (eg decrease by a tablet every month if remain symptom free)

Antihistamines in paediatric population (adapted from BAD guidelines 2021)

Preferred first-line options for children include cetirizine, desloratadine, loratadine, and fexofenadine

Many are licensed for ages 2–11 but ‘when needed, these antihistamines can also be used below age 2 years, despite the licensing age cutoff, given their overall good safety profile’

Administer on a regular, daily schedule using licensed doses based on age and weight

As with adults if symptoms are poorly controlled, carefully increase the frequency up to a maximum of four times a day, adjusting strictly for the child's age and weight

Again its recommended not to combine multiple 2nd generation H1 antihistamines

Antihistamine use in pregnancy

Initial Management Strategy -

• Safety and general principles: Approximately 15% of pregnant women use antihistamines, and there have been no reported birth defects associated with 2nd-generation H1-antihistamines. Their use—even during the first trimester—is not associated with an increased risk of major malformations

• Start with standard doses: The initial management strategy is the same as for the general population: start treatment with standard doses of modern 2nd-generation (non-sedative) H1-antihistamines

• Preferred options (medications of choice): Loratadine and cetirizine are the preferred antihistamines based on safety data and current guidelines

• Updosing considerations (pregnancy):

  • If standard doses are insufficient, consider uptitrating the anti-histamines

  • However, because the safety of these higher-than-approved doses has not been specifically evaluated in pregnant patients, the potential risks and benefits must be discussed with the patient

During Lactation (Breastfeeding)

• Safety and general principles: All H1-antihistamines are excreted into breast milk in low concentrations. 2nd-generation options are advised because their transfer rate to breast milk is minimal and they prevent the infant from suffering adverse side effects.

• Preferred options: Cetirizine, loratadine, and fexofenadine are the most thoroughly studied antihistamines for nursing mothers.

• Updosing considerations (lactation): In refractory (difficult-to-treat) cases, higher doses of 2nd-generation antihistamines might be safely used while nursing, as studies on higher doses of loratadine show minimal transmission into milk.

What to Strictly Avoid

• 1st-generation H1-antihistamines: These should be avoided entirely for both pregnant and lactating women. If taken while breastfeeding, they are transmitted through breast milk and can cause irritability and drowsiness (sedation) in nursing infants.
  
  

Consider montelukast 10mg nocte in addition to a second-generation H1-antihistamine in people whose symptoms are not controlled

Montelukast may be more beneficial in cases where it is exacerbated by aspirin, NSAIDs or in those with delayed pressure urticaria or where angio-oedema is the predominant symptom

Neuro-psychiatric effects can occur in a minority of people, particularly children so counsel parents about this low risk

When prescribing, you must counsel parents and patients to remain highly vigilant for symptoms such as dysphemia (stuttering), nightmares, night terrors, aggression, and sudden behavioural changes

1st generation anti-histamines should not be offered routinely unless there is no alternative due to concerns about short term and long term effects on CNS (sedation, psychomotor impairment and REM sleep disturbance)

This is particularly relevant in the paediatric population

Do not up dose first generation anti-histamines

H2-antihistamines (eg famotidine) are no longer recommended as a standard step in the European urticaria treatment algorithm due to a lack of strong clinical evidence

The current guidelines make no official recommendation for or against combining H1- and H2-antihistamines for patients who do not respond to primary treatments

Despite the low level of published evidence, H2-antihistamines could still be considered as an add on due to their relatively low cost and safety profile but ideally more research would give us a better idea of their efficacy

Can consider very infrequent courses of oral prednisolone lasting only a few days for rescue treatment to control severe exacerbations in addition to anti-histamines

The algorithm in the BAD (2021) algorithm guidelines state that you can add ‘Omalizumab or Ciclosporin’ alongside a 2nd generation H1-antihistamine if first-line options fail

The European guidelines (EAACI) explicitly states that omalizumab should be tried before ciclosporin because ciclosporin has an inferior adverse effect profile and is not licensed for urticaria

Omalizumab is a monoclonal antibody that binds to circulating IgE

By binding free IgE it prevents IgE from attaching to the high-affinity FcεRI receptor on mast cells and basophils

It is licensed as an add-on therapy for chronic spontaneous urticaria in patients aged 12 years and older with an inadequate response to H1 antihistamine treatment

Biosimilar availability: An omalizumab biosimilar (Omlyclo) is now available in the UK and has demonstrated comparable efficacy to the originator in phase III CSU trials

Efficacy:

Effective in approximately 85% of patients, with most experiencing rapid symptom relief — often within the first few weeks of treatment.

Across pivotal phase trials, roughly 50–60% of patients achieve mild disease (UAS7 < 6) and 30–40% achieve complete symptom control (UAS7 = 0) on the 300mg dose

Predicting response - the role of endotypes

The two CSU endotypes (type I autoallergic vs type IIb autoimmune) show different response patterns:

• Type I autoallergic (high total IgE, negative BAT) — fast responders to omalizumab

• Type IIb autoimmune (low IgE, positive BAT, anti-TPO often present) — slow or partial responders to omalizumab; may respond to ciclosporin

Checking total IgE and BAT/BHRA (where available) can therefore help predict who may respond well to omalizumab

UK versus European guideline practical differences

UK prescribing practice around omalizumab is more restrictive than the international (EAACI) guidelines. In the UK, omalizumab is typically given in set 24-week courses after which patients are required to have a treatment break to confirm whether disease is still active — practically this can be tedious for patients who are clearly still symptomatic.

Dose escalation (either increasing to 600mg or shortening the interval to every 2 weeks) is considered off-licence and is not generally permitted — so if the standard 300mg every 4 weeks is not sufficient, the usual next step is to stop omalizumab and switch to ciclosporin.

The EAACI international guidelines are more flexible and explicitly support updosing omalizumab (higher dose, shorter interval, or both) before abandoning it, acknowledging that while this is off-label, patients should be informed and given the chance to respond at a higher dose before moving on to another agent.

Administering omalizumab:

The standard recommended initial dosage is 300 mg administered every 4 weeks.

No routine baseline screening or ongoing blood monitoring is required.

Standard protocol dictates that patients should be monitored under medical supervision for 20 to 30 minutes following their first two to three injections

It is likely that the real-world risk of anaphylaxis in the treatment of CSU is very low

In some cases, what appears to be an adverse reaction may be a small flare-up of urticaria or angioedema immediately following the injection

The risk of anaphylaxis is higher in patients receiving omalizumab for asthma than in those treated for CSU. This may reflect both the more atopic nature of the asthma population and the higher, weight- and IgE-based dosing used in asthma compared with the fixed dose used in CSU

In terms of other side effects, omalizumab is considered very well-tolerated with a strong safety profile, even for long-term use

• Common side effects can include headaches and joint pain

• Infection risk: It may cause reduced immunity against parasitic infections

Ciclosporin is used off-label in urticaria

Generally see response rates of ~40–60%, with some patients experience significant symptom relief within 4 weeks

Dosing: Similar as for eczema = 2.5 - 5mg/kg/day, adjusted based on response and tolerability

Duration: 3-6 months course recommended due to risk of cumulative toxicity with prolonged courses

In general, omalizumab is preferred over ciclosporin as the first step when antihistamines have not worked — it has a better safety profile, does not require blood monitoring, and is licensed for this indication.

Ciclosporin is particularly worth considering in patients who have responded poorly to omalizumab and who have features of the type IIb autoimmune endotype — positive BAT/BHRA, low total IgE, basopaenia/eosinopaenia, or anti-TPO positivity.

This endotype tends to be a slow or partial responder to omalizumab but a better responder to ciclosporin

Dupilumab (Dupixent) is a monoclonal antibody that blocks the shared alpha subunit of the IL-4 and IL-13 receptors, thereby inhibiting signalling from both of these type 2 cytokines

It is already widely used in dermatology for atopic dermatitis and nodular prurigo, and has licensed indications in asthma, chronic rhinosinusitis with nasal polyps (CRSwNP) and eosinophilic oesophagitis.

It has now been approved for chronic spontaneous urticaria in the EU, USA and Japan as an add-on to H1 antihistamines.

Mechanism of action in CSU

By blocking IL-4 and IL-13 signalling, dupilumab is thought to work in CSU through several mechanisms including:

• Reduced B-cell class-switching to IgE and therefore reduced IgE production over time

• Reduced priming and activation of mast cells (as there is less IgE available to bind FcεRI)

• Reduced activation of basophils and eosinophils, which also contribute to the inflammatory milieu in CSU

It is not yet known whether other IL-13-targeting agents have similar efficacy in CSU.

Efficacy — the CUPID trials (LIBERTY-CUPID)

The LIBERTY-CUPID programme comprised three phase 3 trials of dupilumab added to a H1 antihistamine in CSU. The primary endpoint was change from baseline in UAS7

• Study A

  • Omalizumab-naïve patients.

  • Statistically and clinically significant improvement point improvement in UAS7 on dupilumab (-20.5) vs placebo (-12) at week 24

• Study B

  • Patients who were omalizumab-intolerant or had inadequate response to omalizumab.

  • Showed a trend toward benefit but did not meet its primary endpoint

  • Effect size was smaller than in Study A: Dupilumab (-14.4) vs placebo (-.8.5)

• Study C —

  • Repeat study in omalizumab-naïve patients which met the primary endpoint

  • This supported approval in the US and Europe.

When pooled analysis was performed of 289 omalizumab naive patient from the CUPID-A and C study - 43.1% achieved UAS7 ≤ 6 (well controlled) and 30.6% achieved UAS7=0 (urticaria free)

Take home point:

Dupilumab is effective in omalizumab-naïve CSU

Benefit in omalizumab-refractory disease is smaller and less consistent

Consider dupilumab particularly where there is co-existing atopic disease (atopic dermatitis, asthma, CRSwNP).

Extrapolated comparison with omalizumab

Omalizumab remains the most efficacious second-line biologic for CSU on current evidence

Dupilumab can be effective in omalizumab-naïve patients, but benefit in omalizumab-refractory patients appears more modest

Onset of action with dupilumab also appears somewhat slower than with omalizumab or remibrutinib.

Safety

The safety profile in CSU is in keeping with that seen in other indications and is generally very favourable

Conjunctivitis (well recognised in atopic dermatitis) does not appear to have been a significant issue in the urticaria trials.

Where may dupilumab be useful?

• Patients with CSU and co-existing type 2 conditions — atopic dermatitis, asthma, CRSwNP, nodular prurigo — where a single agent can target multiple diseases

• Patients in whom omalizumab has not been tolerated or is contraindicated, bearing in mind that response in the omalizumab-refractory group is less robust

  
  

Remibrutinib is an oral, highly selective Bruton's tyrosine kinase (BTK) inhibitor being developed for CSU

Phase 3 trials are complete and approval is anticipated in the first half of 2026

Mechanism of action

BTK is an intracellular signalling molecule expressed in B cells, mast cells, basophils and eosinophils.

• In mast cells and basophils, BTK sits downstream of the high-affinity IgE receptor (FcεRI) and is essential for transmitting the activation signal that leads to degranulation. Inhibiting BTK therefore reduces histamine and mediator release.

BTK is also essential for B-cell receptor signalling

Inhibition dampens B-cell activation and autoantibody production — this is relevant in CSU because it targets the upstream generation of the IgG autoantibodies that drive the type IIb endotype

Notably, at CSU therapeutic doses remibrutinib doesn't deplete B cells or meaningfully reduce total IgG/IgM/IgE levels — so immune competence is largely preserved.

A key conceptual point: because BTK acts intracellularly, downstream of FcεRI it is effective in both type I autoallergic (IgE antibodies) and type IIb autoimmune (IgG antibodies) endotypes. This makes it a potential attractive option for patients who are slow or poor responders to omalizumab.

Efficacy — phase 3 data

In the phase 3 REMIX-1 and REMIX-2 trials (Metz et al., NEJM 2025), approximately half of patients treated with remibrutinib 25 mg BD achieved well-controlled disease (UAS7 ≤ 6) at week 12 — 49.8% in REMIX-1 and 46.8% in REMIX-2, compared with 24.8% and 19.6% on placebo (both p < 0.001). This response was sustained through week 24

Rapid onset of action was seen with separation from placebo evident as early as week one

Both trials included a 28-week open-label extension in which all patients — including those originally randomised to placebo — received remibrutinib 25 mg BD to week 52, with efficacy sustained throughout and nearly half of treated patients free of itch and hives (UAS7 = 0) by the end of the study.

Approximately one-third of patients in the pooled REMIX population had prior exposure to anti-IgE biologic therapy, and a pre-specified subgroup analysis (Mosnaim et al., JACI 2024) showed remibrutinib was similarly effective in omalizumab-experienced and omalizumab-naïve patients, with UAS7 = 0 achieved in 32.1% versus 28.4% at week 12, supporting its role as an option in omalizumab non-responders.

Comparison with omalizumab

On current cross-trial comparison, omalizumab probably remains the most efficacious second-line agent overall, but remibrutinib appears to be at least as fast-acting as omalizumab and faster than dupilumab. Its oral route is a significant practical advantage.

Safety

Only around one year of safety data is currently available, so long-term safety remains to be established. Issues reported in trials include:

• Transient liver enzyme elevations (generally not exceeding three times the upper limit of normal)

• Mildly increased rate of upper respiratory tract infections. Total IgG, IgM and IgE levels appear stable, but whether vaccine responses are preserved is not yet fully characterised

• Petechiae — reported approximately three times more commonly than placebo, but without clinically significant bleeding issues

Where remibrutinib may be particularly useful

• Patients who prefer (or would benefit from) an oral therapy over injectable biologics

• Patients with type IIb autoimmune endotype features (positive BAT/BHRA, low total IgE, anti-TPO, basopaenia/eosinopaenia) who are likely to be slow or poor responders to omalizumab — as remibrutinib acts downstream of IgE

• Patients who have failed omalizumab

Note: BTK is the same molecule that is defective in X-linked (Bruton) agammaglobulinaemia, and BTK inhibitors are already approved for haematological malignancies including CLL, mantle cell lymphoma, marginal zone lymphoma and Waldenström's macroglobulinaemia

Summary of pivotal trials

Updated treatment algorithm

New international guidelines (publication pending at time of writing) are expected to position omalizumab, dupilumab and remibrutinib as alternative second-line options following uptitrated H1 antihistamines, with choice guided by patient preference, comorbidities and endotype where assessable

Ciclosporin moves further down the algorithm.

With the arrival of omalizumab (and its biosimilar omlyclo), dupilumab and the imminent approval of remibrutinib, third-line agents are now rarely needed in practice

The evidence base for these agents is weak - largely case series and small uncontrolled studies - and most have moved into a "historical" tier in the international guidelines

If a patient has failed uptitrated antihistamines, omalizumab (including uptitration where permitted), dupilumab/remibrutinib where available, and ciclosporin, then options to consider (in no particular order) include:

- Methotrexate

- Azathioprine

- Mycophenolate mofetil

- Dapsone (may have a role in delayed pressure urticaria)

- Narrowband UVB (may have a role in symptomatic dermographism)

- Hydroxychloroquine

- Doxepin (tricyclic with potent H1 antihistamine activity)

- IVIG

- Tranexamic acid (if angioedema is the predominant feature)

At this stage it is worth revisiting the diagnosis — ensure urticarial vasculitis, autoinflammatory syndromes and mast cell disorders have been excluded

General principles

The general approach mirrors that of CSU:

• Avoid the trigger where possible (not always practical - eg friction in symptomatic dermographism)

• Start with a 2nd generation H1 antihistamine, uptitrated up to fourfold if needed

• If antihistamines fail, omalizumab is the next step and is now the best-evidenced second-line option across the inducible urticarias

Omalizumab in CIndU

Although omalizumab is only formally licensed for CSU, there is good evidence supporting its use off-label in CIndU, particularly for the three most common subtypes:

• Symptomatic dermographism - supported by a randomised placebo-controlled trial

• Cold urticaria - supported by a randomised placebo-controlled trial

• Solar urticaria - supported by case series and open-label studies

Evidence is more limited but generally supportive for cholinergic, delayed pressure and heat contact urticarias, and largely anecdotal for aquagenic, vibratory and contact urticarias

In real-world cohorts roughly 70% of CIndU patients achieve a complete or good response to omalizumab, which is broadly comparable to its efficacy in CSU

Reference: Soegiharto R, et al. Omalizumab is effective and safe in chronic inducible urticaria (CIndU): Real-world data from a large multi-national UCARE study. Allergy. 2025.

Subtype-specific considerations

Although the overall approach is similar, a few subtypes have additional or alternative treatment options worth knowing:

• Cholinergic urticaria - consider anticholinergics (eg oxybutynin), beta blockers (eg propranolol), or danazol if antihistamines and omalizumab fail.

Response to omalizumab is less predictable than in dermographism or cold

urticaria

‍ ‍

• Cold urticaria - patients should carry an adrenaline auto-injector given the risk of anaphylaxis. Ciclosporin can be considered as an alternative in refractory cases

‍ ‍

• Delayed pressure urticaria - often the hardest CIndU to treat. Dapsone or sulfasalazine can be considered. Montelukast has some supporting evidence here

‍ ‍

• Solar urticaria - following photoinvestigation to identify the action spectrum, prophylactic phototherapy (hardening using the relevant wavelength) can be very

effective alongside sun avoidance and protection

‍ ‍

• Symptomatic dermographism - narrowband UVB (and failing that PUVA) can be useful as an adjunct

‍ ‍

• Aquagenic urticaria - barrier creams (eg petrolatum) applied before water exposure can be helpful

Future directions

Barzolvolimab, an anti-KIT monoclonal antibody that depletes

mast cells, has shown striking efficacy in early trials for

symptomatic dermographism and cold urticaria and is a

treatment to watch in this space

Angioedema occurring without weals raises a different differential to the urticarial picture, because mediators other than histamine come into play. The main causes are:

• Idiopathic

• Drug induced (eg ACE inhibitors, NSAIDs, antibiotics)

• C1 esterase inhibitor deficiency (hereditary or acquired)

• Hereditary angioedema with normal C1 esterase inhibitor

The bradykinin pathway:

Bradykinin is a vasoactive peptide normally produced at sites of tissue injury. Its job is to cause vasodilation and increased vascular permeability, allowing plasma proteins and immune cells to reach damaged tissue as part of the acute inflammatory response. It is generated through a plasma protein cascade known as the kinin–kallikrein system.

In simple terms:

• Factor XII is activated to Factor XIIa on contact with damaged endothelium

• Factor XIIa converts prekallikrein into kallikrein

• Kallikrein cleaves high molecular weight kininogen to release bradykinin

• Bradykinin binds the B2 receptor on vascular endothelium, causing vasodilation and plasma leakage

Two brakes normally keep this loop in check:

• C1 inhibitor inhibits Factor XIIa and kallikrein, shutting down bradykinin production

• Angiotensin converting enzyme (ACE) degrades bradykinin once it has been produced

In angioedema, bradykinin accumulates either because it is being overproduced (as in C1 inhibitor deficiency, where the brake on kallikrein is lost) or because it is not being broken down (as with ACE inhibitor use, where the enzyme that degrades bradykinin is blocked)

Because this pathway is entirely independent of histamine, bradykinin-mediated angioedema does not respond to antihistamines, adrenaline or corticosteroids

Clinical clues

Most cases of angioedema without weals are idiopathic, but it is important not to miss drug-induced angioedema (eg ACEi, NSAIDs, antibiotics) or C1 esterase inhibitor deficiency, as both can cause life-threatening airway swelling and neither responds to standard angioedema treatment.

Angioedema of the gastrointestinal tract is common in C1 esterase inhibitor deficiency, so always ask about recurrent abdominal pain.

Hereditary angioedema:

Hereditary angioedema (HAE) is traditionally classified into Types I, II and III, and these terms are still widely used.

Note: Current 2025 WAO/EAACI nomenclature unifies Types I and II under HAE-C1-INH (C1 inhibitor deficiency vs dysfunction), and refers to the older "Type III" as HAE with normal C1 inhibitor (HAE-nC1-INH), with subtypes named by their causative mutation

Type I and II are autosomal dominant and due to mutations in the SERPING1 gene, which encodes C1 inhibitor:

• Type I (~85%): C1 esterase inhibitor levels decreased

• Type II (~15%): C1 esterase inhibitor levels normal or increased, but functional levels decreased

Type III (HAE with normal C1 inhibitor) is much rarer. C4 and C1 esterase inhibitor levels are typically normal. Causative mutations include F12 (Factor XII), PLG (plasminogen), KNG1 (kininogen) and ANGPT1 (angiopoietin-1), among others. It is more common in females and can be aggravated by oestrogens.

Acquired angioedema:

Acquired angioedema is due to depletion or destruction of C1 esterase inhibitor through immune complexes or autoantibodies. It is divided into:

• Type I: associated with lymphoproliferative disorders (B-cell lymphoma, NHL, multiple myeloma)

• Type II: associated with autoimmune disease, with autoantibodies against C1 inhibitor

Both types show low C1 inhibitor level and function, low C4, and — importantly — low C1q. The reduced C1q level is what differentiates acquired from hereditary angioedema, where C1q is normal

Investigations:

Practical tips:

• C4 is low both between and during attacks in C1 esterase inhibitor deficiency, making it a useful screening test

• If C4 is low, check C1 inhibitor level and function

• Check C1q if acquired angioedema is suspected

• HAE Type III often requires genetic testing to confirm the diagnosis

Refer all forms of C1 esterase inhibitor deficiency to immunology.

Treatment:

Antihistamines, adrenaline and corticosteroids are largely ineffective in bradykinin-mediated angioedema. Treatment is built around three goals: treating acute attacks, providing cover before known triggers, and reducing attack frequency.

Acute attacks (on-demand):

• C1 esterase inhibitor concentrate (plasma-derived or recombinant)

• Icatibant — a B2 receptor antagonist given subcutaneously, which patients can self-administer

• Fresh frozen plasma is now reserved as a fallback only when specific therapies are unavailable

Short-term prophylaxis (eg before dental work or surgery):

• C1 esterase inhibitor concentrate is preferred

Long-term prophylaxis:

• Modern first-line options are the kallikrein inhibitors lanadelumab (subcutaneous monoclonal antibody) and berotralstat (oral, once daily)

• Newer agents include donidalorsen (reduces prekallikrein production) and garadacimab (Factor XIIa inhibitor given monthly subcutaneously)

• Attenuated androgens (danazol, stanozolol) and tranexamic acid are now considered historical options, used only where modern targeted therapies are unavailable

For acquired angioedema, much higher doses of C1 inhibitor concentrate are typically required, and the underlying lymphoproliferative or autoimmune driver should be sought and treated.

Urticarial vasculitis (UV) is a rare small-vessel leukocytoclastic vasculitis that presents with urticarial wheals but differs from chronic spontaneous urticaria in some important ways

Typical patients are middle-aged women, and it's easily mistaken for CSU at first glance

Clinical clues to UV rather than CSU:

• Individual lesions last more than 24 hours (in contrast to CSU, where wheals come and go within 24 hours)

• Lesions are often painful or burning rather than purely itchy

• Lesions resolve leaving residual petechiae, purpura, or post-inflammatory hyperpigmentation/bruising

• Angioedema occurs in around 50% of UV patients

• Systemic features — fever, arthralgia, malaise, abdominal pain, or eye inflammation

• Raised inflammatory markers (CRP, ESR) — often out of keeping with what you'd expect from CSU

• Dipstick may show blood or protein in the urine

Pathogenesis:

UV is driven by immune complex deposition in small vessel walls, with complement activation and neutrophil recruitment causing leukocytoclastic damage to the vessels themselves. This is what distinguishes it from CSU — in UV you get true vessel wall damage with red cell extravasation, rather than just transient oedema from mast cell degranulation.

Normocomplentaemic UV (NUV)

This is the commonest form, accounting for roughly 70–80% of cases

Complement levels (C3, C4, C1q) are normal

Disease tends to be skin-limited or associated with only mild systemic features such as arthralgia, low-grade fever, or malaise

Prognosis is generally favourable, and the condition is often self-limiting over months to a couple of years

Associations with underlying connective tissue disease are much weaker than hypocomplementaemic UV

Most cases are idiopathic but it can be associated with a range of drugs/conditions

Hypocomplementaemic UV (HUV)

Hypocomplementaemic urticarial vasculitis (HUV) sits in the middle of the urticarial vasculitis spectrum — more clinically significant than NUV but without meeting the full criteria for HUVS

The defining feature is persistent low C3 and/or low C4, reflecting ongoing immune complex-mediated complement consumption

Clinically the skin lesions are similar to NUV but systemic involvement is far more common

Arthralgia and arthritis occur in the majority of patients, and angio-oedema, fever, and malaise are frequent

Extracutaneous organ involvement (pulmonary, ocular, renal, gastrointestinal) is less universal than in HUVS, but a proportion of patients will progress to meet HUVS criteria over time.

Characterised by low C3 and/or C4, with C1q often also reduced. Disease is more likely to be systemic, with arthralgia, fever, abdominal pain, pulmonary and renal involvement.

Around 50% of HUV patients will either have or go on to develop an underlying CTD, so these patients need long-term follow-up and a low threshold for repeat autoimmune serology over time

Hypocomplementaemic urticarial vasculitis syndrome (HUVS)

HUVS is the severe end of the urticarial vasculitis spectrum and is defined by strict criteria (Schwartz criteria):

The hallmark of HUVS is the presence of anti-C1q autoantibodies and markedly reduced C1q — both are relatively specific and help distinguish HUVS from HUV

There is substantial clinical and serological overlap with SLE, and a significant proportion of HUVS patients meet SLE classification criteria either at presentation or over time

Organ involvement in HUVS is multi-system:

HUVS needs a proactive, systems-based assessment at diagnosis — urinalysis, pulmonary function tests, and ophthalmology review — with ongoing multidisciplinary follow-up including rheumatology and respiratory.

Investigations:

If considering Urticarial Vascuilitis a workup could include:

• Skin biopsy — essential for diagnosis. Ideally biopsy a lesion that's been present for less than 48 hours

• FBC, CRP, ESR — inflammatory markers often raised

• Complement levels — C3, C4, and C1q (low C1q suggests HUVS)

• ANA, ENA, anti-dsDNA — to look for SLE or other CTD

• Anti-C1q antibodies — if HUVS suspected

• U&E, urinalysis — to screen for renal involvement

• LFTs, hepatitis B and C serology

• Serum and urine protein electrophoresis — to exclude a paraprotein

• Consider extended workup guided by any systemic features (eg CXR and PFTs is suspect HUVS with respiratory involvement)

Histology:

A skin biopsy is required to confirm the diagnosis, though findings can be subtle and aren't always dramatic. Look for:

• Leukocytoclasia (nuclear dust from fragmenting neutrophils)

• Fibrinoid necrosis of vessel walls (classical but not always seen)

• Endothelial swelling and damage

• Red cell extravasation

• Perivascular neutrophilic infiltrate

Management:

Mild skin-limited disease

Patient is well, no systemic symptoms, normal complement, lesions manageable.

• Non-sedating H1 antihistamines (cetirizine, fexofenadine, bilastine) up-dosed to 4x standard dose, as per chronic urticaria guidelines. Often only partially effective

• Potent topical corticosteroids for individual lesions.

• NSAIDs (e.g. indomethacin) for arthralgia and lesional discomfort — useful adjunct if no contraindications

• Identify and remove triggers

Moderate - Persistent skin disease with mild systemic features

Frequent lesions, arthralgia, fatigue, but no organ-threatening disease.

• Colchicine 500 micrograms BD–TDS — well-tolerated first-line systemic agent. Watch for GI side effects and check renal function

• Dapsone 50–100 mg daily — effective for neutrophil-rich vasculitis. Check G6PD, baseline FBC and LFTs, monitor for haemolysis and methaemoglobinaemia

• Hydroxychloroquine 200–400 mg daily — particularly useful in HUV and when there is overlap with connective tissue disease

• Short prednisolone courses (e.g. 20–30 mg tapering over 4–6 weeks) for flares, but avoid as maintenance

Severe - HUV, organ involvement or refractory disease

Renal, pulmonary, CNS, or ocular involvement, or skin disease refractory to the above.

• Multidisciplinary input: rheumatology, nephrology, respiratory as required.

• Oral corticosteroids (prednisolone 0.5–1 mg/kg/day) to induce remission, with a steroid-sparing agent started in parallel.

• Immunosuppressants: mycophenolate mofetil, azathioprine, or methotrexate

• Rituximab — increasing evidence in refractory HUV and HUVS, particularly with pulmonary involvement

• Omalizumab — case reports and small series suggest benefit in NUV behaving like chronic urticaria; less convincing in HUV.

• IVIG or cyclophosphamide reserved for life- or organ-threatening disease, in conjunction with rheumatology.
  
  

Pathophysiology of Autoinflammatory Urticaria

Autoinflammatory syndromes are characterized by primary dysfunction of the innate immune system. Unlike autoimmune diseases, they lack autoantibodies or antigen-specific T-cell responses

The underlying mechanisms vary. Some, such as CAPS, are monogenic disorders caused by inherited gain-of-function mutations in inflammasome components. Others, such as Schnitzler syndrome and adult-onset Still's disease, are acquired and multifactorial, with disease activity driven by environmental triggers or dysregulated proteins such as a monoclonal paraprotein

Regardless of the initial trigger, the common endpoint is the same: inflammasome hyperactivation (such as the NLRP3 inflammasome) leading to a massive, uninhibited overproduction of pro-inflammatory cytokines, particularly Interleukin-1β (IL-1β)

Clinically, the "urticarial" rashes seen in these syndromes represent a neutrophilic urticarial dermatosis rather than classical histamine-driven mast cell degranulation

They differ from typical spontaneous urticaria in several key ways:

• Lesions frequently cause burning or pain rather than pruritus

• Often persist for >24 hours in a fixed location

• May leave behind residual purpura or hyperpigmentation

• Are notoriously refractory to standard antihistamine therapy

Key Urticarial Autoinflammatory Syndromes

Schnitzler’s Syndrome

A rare, late-onset (acquired) autoinflammatory disorder

Diagnosis typically requires the presence of an urticarial rash and a monoclonal protein, alongside minor clinical criteria

• Rash: Chronic, non-pruritic (or mildly pruritic) urticarial eruption

• Defining Feature: Monoclonal IgM gammopathy (essential for diagnosis; rarely IgG)

• Systemic Symptoms: Recurrent fevers, severe bone and joint pain, lymphadenopathy, and hepatosplenomegaly

• Labs: Markedly elevated acute phase reactants (CRP/ESR) and leukocytosis

Cryopyrin-Associated Periodic Syndromes (CAPS)

CAPS represents a spectrum of rare, autosomal dominant autoinflammatory diseases caused by gain-of-function mutations in the NLRP3 gene. This leads to continuous cryopyrin-inflammasome assembly and uninhibited IL-1β release. Patients present with a non-pruritic, neutrophilic urticarial rash and systemic inflammation.

The CAPS spectrum ranges from mild to severe:

• Familial Cold Autoinflammatory Syndrome (FCAS): The mildest form of CAPS.

  • Features: Episodes of an urticaria-like rash, low-grade fevers, conjunctivitis, and severe arthralgia strictly triggered by generalized exposure to cold temperatures (typically within 1–2 hours of exposure). It usually presents in infancy or early childhood.

• Muckle-Wells Syndrome (MWS): An intermediate severity form of CAPS.

  • Features: Spontaneous, episodic flares of urticarial rash, fevers, and joint pain that are not strictly dependent on cold exposure.

  • Complications: MWS is distinctly complicated by progressive sensorineural hearing loss (typically starting in adolescence) and a high risk of secondary AA amyloidosis, which can lead to renal failure.

• Neonatal-onset Multisystem Inflammatory Disease (NOMID)

  • This is the most severe form of CAPS

  • Characterised by continuous severe inflammation, severe arthropathy, and central nervous system involvement

Adult-Onset Still’s Disease (AOSD)

A rare, polygenic systemic autoinflammatory disorder of unknown etiology, characterized by a classic clinical triad.

• Rash: An evanescent, salmon-pink maculopapular rash that is typically non-pruritic. It characteristically flares in tandem with fever spikes and often appears on the trunk or extremities. (While classic AOSD features this salmon-pink rash, persistent atypical urticarial lesions are also increasingly recognized).

• Systemic Symptoms: Daily high-spiking (quotidian) fevers and severe polyarthralgia/arthritis.

• Labs: Extreme hyperferritinemia (often >1000 ng/mL, with a low proportion of glycosylated ferritin), prominent neutrophilic leukocytosis, and elevated liver transaminases.

Targeted Management

Because the inflammation and cutaneous manifestations in these syndromes are heavily mediated by IL-1 overproduction, standard therapies (such as H1/H2 antihistamines, corticosteroids, or omalizumab) generally yield poor responses.

These conditions typically exhibit a dramatic and rapid response to targeted IL-1 blockade. The mainstays of treatment include:

• Anakinra: A recombinant, non-glycosylated form of the human IL-1 receptor antagonist (IL-1Ra) with a short half-life, administered via daily subcutaneous injection.

• Canakinumab: A human monoclonal antibody that specifically neutralizes IL-1β, administered subcutaneously every 4 to 8 weeks.

Contact urticaria is a wheal-and-flare reaction occurring within minutes of skin or mucosal contact with a triggering substance, usually settling within an hour. The trigger is direct external contact rather than a spontaneous or physical stimulus.

Two mechanisms are recognised:

• Non-immunological — the commonest form. No prior sensitisation needed. Classic culprits are nettles, and preservatives and fragrances in cosmetics and foods (benzoic acid, cinnamic aldehyde, sorbic acid).

• Immunological — IgE-mediated and requires prior sensitisation. The classic trigger is natural rubber latex; foods (fish, shellfish, raw fruit and vegetables) and animal proteins are also recognised. These patients are at risk of anaphylaxis.

Clinical points:

• Suspect in any patient with immediate wheals at sites of contact — hands in occupational cases, perioral with foods

• Take an occupational and exposure history

• Management is trigger avoidance, antihistamines for symptoms, and an adrenaline auto-injector for anyone with a history of systemic reactions

Latex-allergic patients can also react to certain fruits — classically banana, avocado, kiwi and chestnut — due to cross-reactivity between latex and plant defence proteins (the "latex–fruit syndrome"). This can present as oral allergy syndrome, contact urticaria or in a minority - generalised urticaria, angioedema and even anaphylaxis if they ingest large amounts of the food