Chronic Spontaneous Urticaria (CSU)

o Mast cell degranulation is central to the disease process, but other cells are involved

either primarily or secondarily (T cells, B cells, eosinophils, neutrophils,

lymphocytes, basophils, endothelial cells) [1, 3]

▪ Mast cells are located perineuronally and perivascularly, which plays a role in

symptom manifestations (sensory nerve activation → itching, burning,vasodilation → fluid extravasation, cell recruitment) [3]

▪ Mediators: histamine, tryptase, prostaglandins, interleukins, TNF, cell

adhesion molecules, coagulation factors, complement, neuropeptides

(substance P) [3]

o Auto-antibodies (anti-IL-24, IgE and IgG-anti-thyroperoxidase [TPO], IgG-anti

FcεRI and IgG-anti-IgE) have been reported [2-4, 11]

▪ Autoantibodies: found in 25-50%; some may have both IgE and IgG Ab [2, 3, 12]

• Type I auto-immune (auto-allergic): anti-TPO IgE, anti-IL24 IgE

• Type IIa auto-immune: autoantibodies causing cytolysis of target cells

(may overlap with type IIb)

• Type IIb auto-immune: autoantibodies activating mast cells; anti

FcεRI, anti-TPO IgG, anti-IgE IgG; have positive ASST, basophil

histamine release assay

▪ Other available testing: anti-IgE Ab, autologous serum testing (confirms skin

autoreactivity)

▪ Note: Only 8% are diagnosed with autoimmune CSU [13]

o Other serum/plasma factors: directly or indirectly activate cutaneous mast cells

▪ Clotting cascade: activation of extrinsic clotting cascade leading to thrombin

production, which can stimulate C5a generation and thereby increase IgG

dependent histamine release [14]

o Cellular defects: problems with mast cell and/or basophil trafficking, signaling,

function

▪ Cutaneous mast cells have increased histamine release and increased

MRGPRX2 receptors in patients with CSU vs healthy controls [3]

▪ Increase in basophil counts occurred with omalizumab treatment and

correlated with improvement in itch [15]

o Infection: more relevant for acute urticaria in pediatrics [2, 3]

▪ Helicobacter pylori: questionable association with CSU [2, 3, 16]

- Exacerbating factors [2]:

o NSAIDs: usually 1-4H after ingestion (range 15 mins to 24H); may have increase in symptoms for up to 2 weeks after cessation

▪ Non-specific/class effect in approximately 30%, related to COX-1 inhibition

▪ Consider IgE-mediated process if reactivity only to one NSAID

o Infections

o Foods: alcohol, spicy/fermented foods – may be related to vasodilation

▪ If specific, reproducible, and predictable, consider IgE-mediated phenomenon