Definition

  • Urticaria occurring most days of the week for >6 weeks.
  • After exclusion of acute urticaria etiologies and physical urticarias, a cause of chronic urticaria is found in <2% of patients, remaining are termed chronic idopathic urticaria (or chronic spontaneous urticaria in Europe)
  • ~40% of patients with chronic urticaria have angioedema
  • Urticaria activity score:

Urticaria score.png


Differential Diagnosis

  • Chronic exposure to common causes of acute urticaria (e.g. NSAIDs)
  • Chronic (spontaneous) urticaria - <2% with known etiology
    • 25-50% of patients with evidence of autoimmunity (called chronic autoimmune urticaria or chronic autoantibody-associated urticaria):
      • Presence of antithyroid antibodies in 20% (anti-TPO > anti-Tg IgG), anti-FcεR1 (high affinity IgE receptor) IgG or IgM (35-40%), anti-IgE IgG antibody (5-10%)
      • In a retrospective study of 195 adults with CIU for the presence of autoimmune markers: ANA (titer >1:160) was positive in 29%, anti-Tg 6%, anti-TPO 26%, CU Index 38%; CU Index positivity had the strongest association with disease severity (>ANA/Tg/TPO combination > ANA alone)
      • Anti-IgE receptor antibodies may not correlate with disease activity and have been identified in other autoimmune diseases (even in the absence of urticaria), including pemphigus vulgaris, SLE, dermatomyositis, and pemphigoid, suggesting that these antibodies may represent an epiphenomenon.
      • Anti-TPO antibodies are present in ~11% of the general euthyroid population (up to 27% of elderly white women), with only a modest risk for future thyroid disease
      • Significance of autoimmunity unclear for treatment or prognosis, but sometimes referred to as more aggressive or treatment-resistant
    • 55-60% without autoimmunity, described as having true chronic idiopathic urticaria (CIU)
    • ~10% with severe CU have a predominant neutrophilic infiltrate on biopsy; this may be a mild manifestation of urticarial vasculitis and suggests responsiveness to dapsone or colchicine
  • Thyroid disease — controversial, autoimmune thyroid disease associated with chronic autoimmune urticaria, and there are mixed reports regarding the effectiveness of levothyroxine for euthyroid CU patients
  • Physical urticarias and cold-associated urticarias
    • Physical urticaria
      • Delayed pressure urticaria/angioedema — usually associated with CIU, symptoms develop 4-8 hours after pressure stimulus, usually on hands. feet, and buttocks.
    • Cold-associated urticaria
      • Physical cold urticarias
      • Hereditary periodic fever (autoinflammatory) syndromes
        • Cryopyrin-associated periodic syndromes (CAPS) - NLRP3 (also known as NALP3 or cryopyrin) mutations (autosomal dominant) resulting in increased IL-1beta production, treated with IL-1R antagonist (anakinra). CAPS covers a continuum of disease severity with considerable overlap in symptoms and a lack of clear genotype/ phenotype correlation.
          • Familial cold autoinflammatory syndrome (FCAS) - onset in first 6 months, periodic fevers, cold-induced non-pruritic burning papular lesions, leukocytosis, conjunctivitis, arthralgias/myalgias
          • Muckle-Wells syndrome — onset from infancy to adolescence, cold-induced urticarial lesions, deafness (adolescent onset) in 40%, amyloidosis, other systemic symptoms as in FCAS
          • Neonatal onset multisystem inflammatory disease (NOMID), also known as chronic infantile neurologic, cutaneous, articular syndrome (CINCA) - neonatal onset disease with maculopapular exanthema or urticarial rash usually present at birth, aseptic meningitis, arthropathy
        • NLRP12-associated cold-induced autoinflammatory syndrome (FCAS2) - autosomal dominant, cold-induced urticarial rash, arthralgia, myalgia
      • Cryoglobulinemia — cold-induced urticarial or vasculitic lesions commonly associated with hepatitis C

cold urticaria autoinflammatory.png

  • Other autoinflammatory syndromes
    • Adult-onset Still's disease (AOSD) - recurrent fever >39 C for minimum 1 week, pharyngitis, arthralgias, neutrophilic leukocytosis, salmon colored maculopapular rash or urticarial lesions which may appear with nocturnal fevers and decrease in the morning, elevated serum ferritin levels with a reduced glycosylated ferritin fraction
    • Systemic-onset juvenile idiopathic arthritis (soJIA) - intermittent high spiking fever, fleeting maculopapular or urticarial rash, arthritis, elevated serum ferritin levels, in children <16
    • TNF-receptor associated periodic syndrome (TRAPS) - recurrent fever, abdominal pain, arthralgia, annular wandering erythema or urticaria, often periorbital edema
    • Mevalonate kinase deficiency (MKD) - caused by mutation in mevalonate kinase gene
      • Hyper-IgD syndrome (HIDS) - onset in infancy, recurrent fever, abdominal pain, diarrhea, aphthous ulcers and morbiliform rashes, exacerbation after immunization
      • Mevalonic aciduria - HIDS features plus cerebellar ataxia, retardation, hematologic abnormality
Urticaria vs autoinflammatory.png

  • Urticarial vasculitis— Consider when hives are painful or stinging rather than pruritic, last >24-48 hours, leave residual purpura/pigmentation changes, often associated with angioedema. May be associated with autoimmune diseases, and patients often have additional systemic symptoms. Extremely rare in children (<10 cases reported in past 20 years)
    • In contrast to classic description above, a series of UV patients showed 60% with lesions lasting <24 h, 80% with pruritic lesions, and only 8% with painful/tender lesions
    • UV may make up 5-10% of chronic urticaria cases (15% if histamine resistant)
    • Note that large true urticaria may need more than a day to resolve and this should not be confused with vasculitis lesions
  • Mastocytosis (urticaria pigmentosa) — pigmented papules that demonstrate Darier's sign (wheals that appear with stroking of lesion)
  • Polymorphic eruption of pregnancy (PEP) also known as pruritic urticarial papules and plaques of pregnancy (PUPPP) - appears during 3rd trimester or soon after delivery as 1-2 mm erythematous papules within abdominal striae with periumbilical sparing. Lesions then spread to the proximal extremities and coalesce to form urticarial plaques. Half also develop eczematous changes, vesicles, or targetoid lesions. Spontaneously resolves within weeks.
  • HES — cutaneous symptoms may include recurrent urticaria and angioedema (e.g. Gleich syndrome)
  • Celiac disease — case reports of chronic urticaria in children and adults with celiac disease, with resolution of urticaria on gluten-free diet
  • Factor I (C3b inactivator) deficiency — rare autosomal recessive disorder may result in low C3 level, liberation of C3a anaphylatoxin, and can present with urticaria
  • Lymphoproliferative disease/malignancy — rarely have simple urticaria, typically have lesions consistent with urticarial vasculitis, and present with other systemic symptoms
    • Schnitzler's syndrome - onset in 50's, monoclonal IgM or IgG gammopathy with recurrent fever, weight loss, bone pain, myalgias/arthralgias, lymphadenopathy, and non-pruritc urticaria that may become pruritic. May be due to circulating immune complexes and complement activation, anakinra (IL-1R antagonist) effective.
    • Also reported with B-cell lymphomas, Hodgkins, CML, lung/colorectal/liver carcinomas
  • Histamine intolerance — reports of improvement on histamine-free diet
  • Food/drug additive sensitivity — likely to be a rare (or non-factor) in CIU, however there are reports of improvement on a low histamine "pseudo-allergen" free diet
  • Antihistamine sensitivity - cases of challenge-proven urticaria have been reported
  • Chronic infection — in most cases it is not clear whether the two processes are related, occur simultaneously by chance, or are influenced by medications
    • The following infections reported to be associated with urticaria, with improvement after infection resolved:
      • Parasitic
        • Ascaris, Ancylostoma, Strongyloides, Filaria, Giardia lamblia, Entamoeba spp, Blastocystis spp, Echinococcus, Schistosoma, Trichinella, Toxocara, and Fasciola
        • Anisakis simplex (a sea fish nematode) has been reported as possible cause of recurrent acute urticaria in areas of the world where uncooked fish is eaten frequently
      • Bacterial: H. pylori, Streptococcus spp, Staphylococcus spp, Yersinia enterocolitica, Mycoplasma pneumonia
        • In a meta-analysis, rate of CU remission when H. pylori was eradicated was 30.9% vs. 21.7% when not
      • Viral: hepatitis C, CMV, EBV, norovirus, parvovirus B19
      • Unspecified organisms: tonsillitis, sinusitis, dental infection, UTI
      • Fungal: The existence of an ‘id’ reaction with urticaria secondary to a fungal infection is no longer considered tenable (Kaplan)



Diagnostic Approach


ACAAI/AAAAI Practice Parameter 2013

  • Limited non-specific laboratory evaluation
    • CBC with diff
    • ESR
    • TSH
    • BUN/Cr
    • LFTs
  • A thorough history and meticulous physical exam is essential for determining whether additional tests are appropriate:
    • Skin biopsy
    • Physical challenge tests
    • C3, C4, and CH50
    • Functional autoantibody assay (for autoantibodies to FcεRI) and/or ASST
    • Stool O&P
    • UA
    • Hepatitis B and C serologies
    • CXR and/or other imaging studies
    • ANA
    • RF, Anti-CCP
    • Cryoglobulin levels
    • Serologic and/or skin testing for immediate hypersensitivity



WAO Guideline 2012

  • History/physical exam
    • Time of onset
    • Frequency and duration of wheals
    • Presence of diurnal variation
    • Shape, size, and distribution of wheals
    • Associated angioedema
    • Family and personal history of urticaria
    • Atopy
    • Medications (NSAIDs, hormones, laxatives, immunizations)
    • Observed correlation with food and stress
  • Diagnostic studies
    • CBC/diff
    • LFTs
    • ESR, CRP
    • Screening for thyroid autoimmunity "may be considered" (Anti-Tg, Anti-TPO)
    • Physical urticaria testing
    • Role of H. pylori is controversial, and the evidence is weak
    • Skin biopsy may be needed to confirm urticarial vasculitis or Schnitzler syndrome


Kaplan

  • CBC/diff - high eosinophil counts might trigger a stool examination for ova and parasites
  • CRP or ESR
  • TSH/FT4, anti-TPO, anti-TG antibodies - may be useful because so many CU patients are found to be hypothyroid and are then treated with a thyroid hormone
  • Other tests
    • Routine food allergy skin testing - not recommended
    • ANA - not recommended in the absence of symptoms (other than urticaria) that might suggest the presence of SLE
    • Anti-IgE/anti-IgE receptor antibodies - of theoretical interest, but none of the treatment modalities distinguish patients with the antibodies from those without them
    • Skin biopsy - when the diagnosis is not clear or when a vasculitis is suspected or at least needs to be ruled out
      • Examples of circumstances where a skin biopsy should be performed would be the presence of fever, concomitant petechiae or palpable purpura, lesions that fade with bruising, individual lesions lasting >24 h (and certainly >36 h), or prominent arthralgia
      • ANA, C3, C4, and C1q binding assay for circulating immune complexes and cryoglobulin determination would be included


Saini

  • History/physical exam
    • Duration of episodes and lesions appearance (photos)
    • Medication/food history
    • Identify physical triggers (significant in 20%)
    • Consider infections
  • Possible Lab Studies
    • Basic series: CBC/diff, BMP, LFTs, UA
    • Other testing guided by physical exam or history
    • Extended: ESR, Anti-Tg, Anti-TPO, TSH, C3, C4
    • Consider "autoimmune" tests: basophil CD203c level or CU index
    • Skin biopsy to exclude urticarial vasculitis or define cellular picture in atypical cases (elevated CRP or ESR, unresponsive to antihistamines, lesion duration >24h, painful rather than pruritic, petechial or purpuric changes, leave residual pigment changes).
      • Peroni: Up to 40-60% of patients with UV may present only with wheals, therefore, a skin biopsy should be considered in all cases of otherwise clinically typical chronic urticaria, especially if the urticaria is resistant to antihistamines
      • Procedure
        • 3 mm punch biopsy from a fresh lesion. Patients receiving steroids may need to discontinue these medications to allow new lesions to form.
        • Biopsy specimens should be submitted in formalin for routine H&E staining and in those patients in whom urticarial vasculitis is a strong consideration, in Michel’s media or freshly snap frozen for DIF microscopy.


Bernstein

  • History/physical exam
  • Evaluate for evidence of physical urticarias, dermatographism
  • Initial testing
    • CBC/diff
    • ESR
    • TSH
    • LFTs
    • UA
    • Allergy skin testing is not indicated in the initial evaluation of urticaria
  • Testing for refractory cases
    • C4
    • Anti-Tg, Anti-TPO
    • H. pylori antibodies
    • Hepatitis panel
    • Consider autologous serum skin test
    • Consider skin biopsy if urticaria are atypical, not evanescent


Dreyfus

  • Initial testing
    • TSH, Anti-Tg
    • CBC/diff
    • SPEP
    • LFTs
    • Hepatitis titers
    • H. pylori IgG, IgM and titers for other infectious illness - if suggested by history
    • ANA and anti-DNA anti-bodies - if history or exam suggestive of vasculitis
    • C1INH level and function, C2, C4 - if angioedema present
    • Chromagranin A or urine catecholamines - if significant flushing, carcinoid features
    • Tryptase - if significant component of anaphylaxis with urticaria, angioedema
    • CXR and PFT - if associated respiratory symptoms such as cough, wheezing
    • Total immunoglobulin levels, B/T cell subsets - if history suggestive of parasitic infection, chronic infection
    • Pregnancy testing - if relevant age and sex
    • Serum basophil activation or histamine release in vitro and/or autologous skin testing - not required but may be useful to confirm diagnosis


EAACI/WAO Guideline (2013)

  • Routine diagnostic tests:
    • CBC/diff
    • ESR or CRP
    • Omission of suspected drugs (e.g. NSAID)
  • Extended diagnostic program for identification of eliciting factors and for ruling out possible differential diagnoses if indicated:
    1. Infectious diseases (e.g. Helicobacter pylori)
    2. Test for type I allergy - rare cause of chronic urticaria in patients with daily or almost daily symptoms, but must be considered in patients with intermittent symptoms
    3. Functional autoantibodies
    4. Thyroid hormones and autoantibodies
    5. Skin tests including physical tests
    6. Pseudoallergen-free diet for 3 weeks
    7. Tryptase level
    8. Autologous serum skin test
    9. Lesional skin biopsy


Diagnostic Approach for Children (Boguniewicz)

  • Routine testing
    • Allergy testing
    • CBC/diff
    • ESR
    • LFTs
    • TSH, FT4, anti-Tg, anti-TPO
  • Extended testing for selected patients
    • Hepatitis serology
    • Complement levels
    • ANA and specific autoimmune testing
    • EBV testing
    • Stool ova and parasites
    • Skin biopsy if vasculitis or mastocytosis are suspected
  • Children whose CU persists should have yearly re-evaluation to rule-out late onset autoimmune disease

Specialized Lab Testing for Urticaria

  • CU Index - patient's serum is added to healthy donor basophils and quantity of histamine release is measured. The reference range for a healthy non-CU population is <10. Values ≥10 indicate that basophils were stimulated by patient serum to release histamine (the larger the value the more histamine released).
    • In one study, 23% of healthy controls vs. 57% of CU patients had a positive CU index
    • Positive CU Index associated with more severe CIU
  • Anti-FcεR1 (high affinity IgE receptor) IgG antibody- by Western blot, direct measurement of IgE receptor autoantibodies
    • These antibodies may not correlate with disease activity and have been identified in other autoimmune diseases (even in the absence of urticaria), including pemphigus vulgaris, SLE, dermatomyositis, and pemphigoid, suggesting that these antibodies may represent an epiphenomenon.
  • Anti-IgE IgG antibody
  • Basophil CD203c levels - by flow cytometry, indirect measure of autoantibodies to IgE receptor which result in basophil activation.
  • Anti-C1q antibody - Patients with hypocoplementemic urticarial vasculitis syndrome (HUVS) usually have autoantibodies reactive with the collagen-like region of the C1q molecule, and can develop angioedema.


Additional Testing Notes

  • D-dimer - elevated D-dimer may be a biomarker of antihistamine-resistant chronic urticaria (Asero)
    • This subtype may respond to anticoagulation with tranexamic acid and low molecular weight heparin
  • Wedi - careful search for at least infections with H. pylori, strep, and perhaps also staph and yersinia should be included in the work-up of severely affected patients; our routine work-up includes:
    • Helicobacter pylori monoclonal stool antigen test
    • Serology for strep (ASO, anti-DNase B), staph (antistaphylolysin), yersinia (IgA, IgG, immunoblot). If an infection is identified, it should be appropriately treated and it should be checked whether eradication has been achieved.
  • Initial evaluation for autoinflammatory syndromes (e.g. CAPS) should include:
    • CBC/diff - to screen for neutrophilia
    • CRP, ESR
    • ANA - help rule out autoimmune disease
    • UA - screen for proteinuria which suggests renal amyloidosis
    • Serum amyloid A level - inflammation marker and screening parameter for amyloidosis
    • Gene mutation analysis if specific diagnosis suspected (e.g. CAPS)


Treatment and Prognosis




References



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