Introduction

Pathogenesis

‍ ‍Pathogenesis classification

‍ ‍Immunological

‍Clinical classification

Acute urticaria

Chronic urticaria

‍ ‍ Idiopathic (chronic spontaneous urticaria)

‍ ‍Inducible

Triggers and associations

Management intro

‍ ‍Investigations

‍ ‍First line Treatment (H1 anti-histamines, montelukast, H2 anti-histamines, oral steroids)

‍ ‍Second line Treatment

‍ ‍Ciclosporin

‍ ‍Omalizumab

‍ ‍Third line treatment

‍ ‍Specific treatment inducible urticarias

‍ ‍

Angioedema without wheals

Urticarial vasculitis

Autoinflammatory syndromes

Contact urticaria

Presents as a very itchy rash that consists of transient weals (‘hives’)

Clinically you get a ‘wheal and flare’

• The wheal refers to the raised, itchy and often pale central area of the hive (puffy skin)

• The flare is the red, inflammed area often surrounding the wheal

The appearance of the flare is due to dilatation of blood vessels and the wheal is due to swelling of the superficial dermis (papillary dermis) due to increased vascular permeability allowing fluid escape into the surrounding tissue

Individual lesions tend to resolve within 24 hours

It can be classified in different ways:

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’)

Based on pathogenesis: Immunologic, non-immunologic or inducible (eg physical)

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 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

Immune complexes (formed from antibody-antigen binding) can activate the complement cascade.

This generates C5a, a small protein fragment known as an anaphylatoxin. C5a binds directly to C5a receptors (C5aR) on the mast cell surface, causing degranulation and histamine release without any IgE involvement.

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

Because the mast cell activation occurs through C5aR rather than through the IgE/FcεRI pathway, it can be resistant to standard antihistamine therapy.

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:

Urticaria-like rashes can also be a presenting feature of autoinflammatory syndromes such as Schnitzler syndrome, cryopyrin-associated periodic syndromes (CAPS) and adult-onset Still's disease. These conditions are discussed in more detail later in this chapter.



Non-immunologic

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 G-protein coupled 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.

Approximately 33% of people with chronic spontaneous urticaria have functional histamine-releasing IgG autoanbodies 

This subgroup of patients may have a more intense and protracted disease course

• Can get IgG antibodies against IgE receptors

• Can get antibodies against IgE (anti-IgE antibodies) 

3. Immune complexes:

An antibody and antigen form an immune complex which can trigger the complement pathway

This can lead to increase in C5a (anaphylotoxin) which causes mast cell degranulation

Causes:

• Infection - hep C, hep B, EBV

• Urticarial vascultiits

• SLE

• Serum sickness

Innate immune response:

Autoinflammatory 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

Examples of autoinflammatory syndromes causing urticaria:

Shnitzler syndrome

Cryoprin associated periodic syndromes

Spontaneous urticaria:

• Acute

• Chronic (6 weeks or more of continuous activity)

• Episodic (acute intermittent or recurrent activity)

Inducible urticarias (usually chronic)

• Will discuss in more detail later

Angio-oedema without weals:

• Idiopathic

• Drug induced (eg ACEi)

• C1 esterase inhibitor deficiency (hereditary or acquired)

• Hereditary angioedema with normal C1 esterase inhibitor

Disease processes presenting with urticaria-like rashes:

• Urticarial vasculitis

• Autoinflammatory syndromes (Shnitzler’s, CAPS, adult onset Still’s)

Contact urticaria

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, strawberries, 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

> 6 weeks

1/ Idiopathic (chronic spontaneous urticaria):

Commonest type chronic urticaria

Can get angioedema

Natural history:

At least 50% resolve over 6-12 months

Another 20% resolve by about 3 years

Another 20% resolve (90% overall) by about 5 years

Small proportion will be persistent

Unfortunately, even if it resolves it often recurs

2/ Inducible urticarias (30%)

Usually chronic

Weals reproducibly induced by same physical stimulus

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

(except delayed pressure urticaria: 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 urticaria, angioedema and even anaphylaxis (eg someone with cold water urticaria jumping into a plunge pool or going cold water swimming)

Can be confirmed on provocation testing

Types of inducible urticarias:

• Dermographism (minor trauma)

  • Stroke the skin and get wheals

  • Can be demonstratable in clinic

  • Mucus membranes very rarely affected

Other inducible urticarias:

• Acquagenic (contact with hot or cold water)      

• Cold contact (cold water, cold wind)

• Heat contact (hot bath/shower) 

• Vibratory urticaria (vibrating tools)

• Solar urticaria (sunshine)

• Delayed pressure (sitting, lying, tight clothing)

• Cholinergic (exercise, emotion)

• Exercise induced anaphylaxis

History and exam is key

Assess impact on quality of life (eg DLQI)

Activity of disease should be measured if considering 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), tinea infection, UTIs, sinusitis

• Medications - NSAIDs, Opioids

• Alcohol, Spicy foods

• Heat, exercise

• Tightly fitting garments

Associations:

Significant association between chronic urticaria and autoimmune thyroid disease so may investigate for this (TFTs and thyroid autoantibodies)

H. pylori

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

Of note:

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

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

There are rare exceptions:

• Reaction to omega-5 gliadin (wheat), lipid transfer protein (plant derived food) or crustacea (prawns)

• Can present as intermittent exercise induced urticaria/anaphylaxis (exertion being required for reactions to occur)

• Allergy to aGAL in red meat can also cause a delayed reaction with urticaria (rare in UK)
  
  

Acute/episodic spontaneous urticaria:

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

FBC, CRP/ESR may help identify infective cause

Chronic spontaneous urticaria:

FBC

• Eosinophils: drug-induced, parasitic, pre-bullous pemphigoid

• Leucocytosis: infection, urticarial vasculitis

• Leucopaenia: SLE

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

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)

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

If > 40 years and have systemic symptoms (eg fever, polyarthralgia, lymphadenopahthy) should do immunoglobulins and SPEP (? IgM paraprotein of Shnitzlers)

Inducible urticarias:

Do appropriate provocation tests where appropriate and if set up for this:

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

• Deromgraphism - lightly scratch skin and wait up to 10 minutes

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

• Cholinergic - exercise patient in warm environment

Consider extra investigations depending on type of inducible urticaria

• Cold contact urticaria (consider cryoglobulins)

• Solar urticaria (ANA and porphyrins +/- referral to specialist centre to consider phototesting)

• Aquagenic pruritus (Annual FBC as can be associated with PRV, other haem disorders)

Biopsy:

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

2nd generation H1-antihistamines:

Offer a 2nd geneartion H1-antihistamine using the regular daily licensed dose

Offer updosing by up to fourfold in people whose symptoms are still inadequately controlled by standard dose (provided it is tolerated and there are no cautions/contraindications)

Suggest continuing anti-histamines regularly even if not getting lesions for a period of time

Offer progression of therapy, through first-line treatment options every 2-4 weeks

Attempt stepwise dose reduction following complete symptom control

Consider switching from one-second generation H1-antihistamine to another in people whose symptoms do not respond adequately to, or do not tolerate the first drug

Insufficient evidence to make a recommendation on using two different 2nd-gen H1 anti-histamines at the same time

In pregnancy and breastfeeding:

Insufficient evidence to make recommendation

If active disease and after counselling: consider lowest dose possible of cetirizine or loratadine

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

Others:

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)

Do not updose first generation anti-histamines

H2-receptor blockers:
Insufficient evidence to recommend routine addition of H2-antihistamines if poorly controlled but may be considered if associated with dyspepsia (which should be investigated)

Famotidine 40mg once daily preferable to cimetidine as latter interacts with cytochrome p450 system

(ranitidine has been removed from manufacturing)

Oral steroids:

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

Offer omalizumab or ciclosporin depending as appropriate

Avoid long-term use of ciclosporin if at all possible (if not use lowest effective dose and interrupt treatment periodically to confirm continued requirement)

Offer for 3-6 months in addition to H1 anti-histamines

Use similar dose as use in eczema (approx. 4-5mg/kg)

Better for autoimmune urticarial than chronic spontaneous form

Ideally only use for a short period of time (kidney and BP problems)

If need for longer - use lowest effective dose and interrupt treatment periodically to confirm continued requirement and consider alternative agents

For more information on ciclosporin, click on link

Anti IgE monoclonal antibody

It binds to the part of IgE that would usually bind to the mast cell receptor

Available for asthma since 2003

Licensed as an ‘add on therapy for treatment’ of chronic spontaneous urticaria (12 years and older) with inadequate response to H1 antihistamine treatment

Phase III, double blind, RCTs:

ASTERIA I and II:

Significant improved outcomes for itch severity scores

GLACIAL (n=336)

Significant improvmeent in both UAS7 score and weekly ISS score

Unfortunately the itch score did often increase when omalizumab was stopped

Indications:

Patient > 12 years of age

UAS7 score > 28

No response to standard treatment with H1 antihistamines (up to x 4 licensed dose) and/or leukotrine receptor antagonists and/or H2 antihistamines

Contraindications:

Hypersensitivity to omalizumab

Breastfeeding or pregnancy

(avoid unless necessary after consideration of benefits and risks. Currently there is no evidence that it is harmful to baby)

Dosing:

Subcutaneous injection 300mg (x2 150mg injections) once every 4 weeks

4-6 month course

One potential protocol (as per GGC protocol in West of Scotland):
After 4th dose (week 16) you check UAS7 at week 20

If UAS < 16: continue omalizumab

If UAS > 16 patient is a classified a non-responder and may need new treatment

In some cases may continue:

• UAS7 16-27 but had baseline score in excess of 40

• If a patient is steroid or immuno-suppressive dependent and unable to stop treatment without severe symptom relapse then omalizumab can be considered to minimise long term risks of therapy

• With a large angio-oedema component seeing as it is not recorded on UAS7

After 6th dose (week 24):

If patient is in remission stop the omalizumab with phone review at 6-8 weeks and appointment in clinic in 3 months

If not in remission or the condition relapses a further course of omalizumab may be indicated

Following treatment:
UAS7 scores should be carried out monthly after completing a full course of omalizumab to assess if symptoms have relapsed despite taking antihistamines

A decision to start another course of omalizumab will be based upon a qualifying UAS7 score

Monitoring whilst receiving omalizumab:

Blood pressure, pulse and O2 sats should be monitored pre and post injection

First three doses given in hospital:

• 1st injection: remain in department for 2 hours for observation

• 2nd-3rd injections: remain in department for 30 minutes

• From fourth dose onwards may be suitable for patient to self inject at home

No routine blood tests are necessary

SEs:

Usually well tolerated with relatively few side effects

Can get small injection site reaction shortly after it is given

Anaphylaxis reported in asthma patients receiving omalizumab (hence reasons for monitoring first few doses)

Headaches, sore throat, ‘flu like symptoms’, arthralgia, sinusitis, fever, abdominal pain have been reported

Drug interactions:

No known interactions with other medications

Consider if 1st and 2nd line fail

Narrowband UVB

MTX

Dapsone

Azathioprine

MMF

Others include: Doxepin, Hydroxychloroquine, IVIG, tranexamic acid (if pre-dominantly angioedema)

Cholinergic - consider anticholinergic drugs (eg oxybutinin), beta blockers (eg propranolol), danazol, possibly phototherapy

Cold urticaria - consider ciclosporin

Delayed pressure urticaria - consider dapsone or sulfasalizine

Solar urticaria - Consider UV prophylactic phototherapy using the relevant wavelength of light for that person following photoinvestigation, offer advice about sun avoidance/protection

Symptomatic deromgraphism - consider narrowband UVB (failing that could consider pUVA)

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

In angioedema, excessive bradykinin accumulates either because it is being overproduced (as in C1 esterase inhibitor deficiency, where the normal 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.

Usually no cause is identified but it is important not to miss cases of drug-induced angio-oedema (eg ACEi, NSAIDs, antibiotics) or C1 esterase inhibitor deficiency as both can cause life-threatening airway swelling and neither respond to usual angio-oedema treatment

Angio-oedema of the GIT is common in C1 esterase inhibitor deficiency so ask about GI symptoms

Hereditary angioedema:

Type I and II due too mutations in SERPING 1 gene involved in production of C1 inhibitor

Type I (85%): C1 esterase inhibitor decreased

Type II: C1 esterase inhibitor levels normal or increased but functional C1 esterase inhibitor levels decreased

Anti-histamines, adrenaline and steroids don’t tend to be effective in controlling symptoms

Treatment includes:

C1 esterase inhibitor during an acute attack

FFP prior to surgical interventions

Prophylaxis with attenuated androgens such as danazol/stanozolol

Type III:

Is exceptionally rare and can be associated with normal levels of both C4 and C1 esterase inhibitor level

Due to factor XII mutation

F > M

Can be aggravated by oestrogens

Type 1: C1 esterase inhibitor decreased, C1 esterase inhibitor function decreased, C4 decreased, C1q normal

Type 2: C1 esterase inhibitor level normal or high, C1 esterase inhibitor function decreased, C4 decreased, C1q normal

Type 3: Normal C4 and C1 esterase inhibitor

Acquired angioedema:

Due to destruction of C1 esterase inhibitor function through immune complexes or autoantibodies

Divided into 2 types

Both types are associated with low C1 esterase inhibitor level and function and low C4

Type 1: Associated with lymphoproliferative disorders (B-cell lymphoma, NHL, Multiple myeloma)

Type 2: Associated with autoimmune disease

Acquired angioedema is associated with a positive anti-C1q antibody and reduced C1q levels

This can help differentiate it from hereditary angioedema

Treatment: Requires much higher amounts of C1-INH concentrate

Acquired angioedema: Low C1-inhibitor levels, Low C1-inhibitor function, low C4, low C1q

Investigations angio-oedema without weals:

Get low C4 both between and during attacks in C1 esterase inhibitor deficiency

If C4 low check C1 esterase inhibitor level and function (decreased level in type I, decreased function in type 2)

C1q levels (can be decreased in acquired C1 esterase inhibitor deficiency)

Refer all forms of C1 esterase inhibitor deficiency to immunology

Lesions persist for more then 24 hours and leave petechia/purpura

Lesions can be tender and painful

Can get symptoms and signs of underlying disease (fever, malaise, arthralgia, hypertension, blood/protein in urine)

Can be associated with other underlying diseases

Will often have high inflammatory markers

Due to small vessel damage by PMNs in a vasculitis and get leakage of red blood cells

Won’t respond to anti histamines and probably other systemic treatment (eg steroids)

If suspect urticarial vasculitis a skin biopsy should be performed to confirm the diagnosis

Investigations urticarial vasculitis:

Skin biopsy required to confirm diagnosis (changes often subtle: look for leucocytoclasia, endothelial cell swelling or damage, red cell extravasation or fibrin deposition)

CRP, ESR often high

Perform full vasculitic screen (looking for underlying connective tissue disease or infection)

Low C3/C4 and positive anti-C1q antibodies may indicate hypocomplemantaemic urticarial vasculitis which is more severe and has higher association with systemic disease (especially SLE)

Can present clinically with urticaria-like rashes and include:

• CAPS (hereditary - usually onset in childhood, although can get late-onset acquired disease)

• Schnitzler syndrome (acquired with late onset)

• Adult onset Stills disease (acquired)

CAPs consists of 3 overlapping conditions:

• Familial cold autoinflammatory syndrome

• Muckle-Wells syndrome

• Neonatal-onset multi inflammatory disorder

These are all usually accompanied by fever, malaise and high levels of inflammatory markers

May present with red eyes, renal impairment, deafness, pyrexia

Schnitzler’s syndrome:

Symptoms and signs:

Fever

Urticaria

Bone pain/arthralgia

Associated with underlying IgM paraproteinaemia

Still’s disease:

May present with an atypical urticarial type of rash or an evanescent, salmon-pink maculopapular type of rash

Also may have a sore throat, arthralgias, lymphadenopathy and a negative RF

Autoinflammatory syndromes investigations:

CRP/ESR usually elevated

Serum amyloid A (often elevated)

Immunoglobulins and SPEP (Shnitzlers) - low-level IgM can be difficult to detect

Genetic tests if CAPS suspected (refer to appropriate centre)

Get urticaria at the site of of contact of a trigger

Anaphylaxis can occur

Onset is rapid (within minutes) and reactions usually last < than 2 hours

Unlike inducible urticarias the disease is acute and the trigger is not physical and can be due to a large variety of substances (eg food, plants, animals, fragrances, preservatives)