Chronic spontaneous urticaria: update on pathogenesis and therapeutic implications

Criado, Paulo Ricardo; Criado, Roberta Fachini Jardim; Miot, Hélio Amante; Abdalla, Beatrice Martinez Zugaib; Marchioro, Helena Zenedin; Bonamigo, Renan Rangel

doi:10.1016/j.abd.2025.501198

person Paulo Ricardo Criado *

Study design · drafting · editing of the manuscript · and approval of the final version of the manuscript

schoolCentro Universitário Faculdade de Medicina do ABC, Santo André, SP, BrazilschoolFaculdade de Ciências Médicas de Santos (Fundação Lusíada), Santos, SP, Brazil

0000-0001-9785-6099

person Roberta Fachini Jardim Criado

Study design · drafting · editing of the manuscript · and approval of the final version of the manuscript

schoolCentro Universitário Faculdade de Medicina do ABC, Santo André, SP, BrazilschoolAlergoskin Alergia e Dermatologia, UCARE Center and ADCARE, Santo André, SP, Brazil

0000-0003-2482-3047

person Hélio Amante Miot

Study design · drafting · editing of the manuscript · and approval of the final version of the manuscript

schoolDepartment of Infectology, Dermatology, Diagnostic Imaging and Radiotherapy, Faculty of Medicine, Universidade Estadual Paulista, Botucatu, SP, Brazil

0000-0002-2596-9294

person Beatrice Martinez Zugaib Abdalla

Study design · drafting · editing of the manuscript · and approval of the final version of the manuscript

schoolCentro Universitário Faculdade de Medicina do ABC, Santo André, SP, Brazil

0000-0003-4586-1915

person Helena Zenedin Marchioro

Study design · drafting · editing of the manuscript · and approval of the final version of the manuscript

schoolDermatology Residency, Hospital Irmandade Santa Casa de Misericórdia de Curitiba, Curitiba, PR, Brazil

0000-0002-2756-053X

person Renan Rangel Bonamigo

Study design · drafting · editing of the manuscript · and approval of the final version of the manuscript

schoolService of Dermatology, Santa Casa de Porto Alegre, Porto Alegre, RS, BrazilschoolService of Dermatology, Hospital de Clínicas, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil

0000-0003-4792-8466

Editor

Ana Maria Roselino.

person* Corresponding author.
E-mail:prcriado@uol.com.br (P.R. Criado)

Conflicts of interest

Paulo Criado: Advisory board ‒ Pfizer, Galderma, Takeda, Hypera, Novartis, Sanofi; Clinical research - Pfizer, Novartis, Sanofi, Amgen and Lilly; Lecturer: Pfizer, Abbvie, Sanofi-Genzyme, Hypera, Takeda, Novartis.

Roberta Fachini Jardim Criado: Advisory board ‒ Pfizer, Takeda, Hypera, Novartis, Sanofi; Clinical research - Pfizer, Novartis, Sanofi and Lilly; Lecturer: Pfizer, Abbvie, Sanofi-Genzyme, Hypera, Takeda, Novartis.

Hélio Miot: Advisory Board - Johnson & Johnson, L’Oréal, Theraskin, Sanofi e Pfizer; clinical research Abbvie, Galderma and Merz.

Beatrice Martinez Zugaib Abdalla - No conflicts of interest declared.

Helena Marchioro - Advisory Board - Novartis and UCB Pharm; Lecturer: Johnson & Johnson, Novartis and UCB Pharma.

Renan Bonamigo - No conflicts of interest declared.

Receptors and Type of Mediators	Name	Functions/Actions
Immunoglobulin superfamily receptors	FcɛRI	Expressed on mast cells and basophils as a tetramer composed of subunits (αβγ2), the α subunit responsible for binding the FcɛRI receptor to IgE, the β subunit for regulating receptor expression and signaling, and the γ subunit responsible for signal transduction. FcɛRI circulates free in the blood, either in a soluble form (sFcɛRI) or bound to IgE. IgE binds to FcɛRI with high affinity (Kd ∼10-9 to 10-10), and the dissociation half-life of IgE from FcɛRI is very slow, on the order of weeks. Due to IgE's high affinity for the receptor and slow dissociation, there is long-lasting sensitization of mast cells exposed to specific antigens.
Immunoglobulin superfamily receptors	FcγRIII	When activated by IgG1, in mice, it promotes anaphylaxis
G protein-coupled receptors	Mas-related G protein-coupled receptor X2 (MRGPRX2)	Expressed predominantly in mast cells of the skin, peripheral neurons, basophils, and eosinophils. Activated by eosinophil major basic protein (MBP) and eosinophil cationic protein, fluoroquinolone antibiotics, opioids, neuromuscular blockers, human β-defensin 2 (hBD2), cathelicidin (LL-37), neuropeptides (such as substance P), Calcitonin Gene-Related Peptide (CGRP), Vasoactive Intestinal Substance (VIP), Staphylococcus aureus δ-toxin, hormone receptor modulators, phenothiazines, corticostatin-14, icatibant, cetrorelix, leuprolide, octreotide, sermorelin, atracurium, tubocurarine, rocuronium, and herbal medicines.
	Histamine receptors H1, H2 and H4 (H1R, H2R and H4R)	The binding of histamine to its H1R on mast cells stimulates the release of more histamine and other mediators, increasing the expression of cell adhesion molecules and chemotaxis of eosinophils and neutrophils, in addition to increasing antigen presentation capacity and costimulatory activity in B cells, and suppressing IgE production. Histamine binding to the H2R inhibits mast cell chemotaxis, as well as that of eosinophils and neutrophils, suppressing Th2 responses. Stimulation of the H4R leads to increased intracellular calcium influx, mast cell degranulation, and the release of cytokines, cysteinyl leukotrienes, and leukotriene B4 (LTB4). It is also relevant to the histaminergic pathways of cutaneous sensory nerve endings that conduct pruritus.
	Adenosine receptor (A3R)	Adenosine receptors differ in the type of G protein they recruit, their effect on adenylyl cyclase (AC) activity, and the downstream signaling pathway they trigger. Adenosine can both increase and inhibit mast cell degranulation, indicating that its effects on these receptors are controversial and still need to be clarified. Depending on the study model, A1, A2b, and A3 receptors demonstrate anti- or pro-inflammatory activity.
	Cystil-Leukotriene Receptors	Cysteinyl leukotrienes (CysLTs), released from mast cells, are important mediators of allergy. Type 1 receptors for CysLTs (CysLT1Rs) are involved in accelerating IgE-mediated MC activation.
	Protease-activated receptor (PAR) types 2 (PAR2) and 4 (PAR4)	PAR2: can be activated by proteases (chymase, tryptase)
		PAR4: activated by thrombin.
	Corticotropin-releasing factor (CRF) receptor	CRF1 receptor: induces the release of VEGF. They are co-receptors of VEGFR-2.
	Calcium sensor (CaS)	Increases mast cell activity.
	Serotonin receptor (5-HTR)	Amplifies mast cell activation
	Acetylcholine receptor (Muscarinic M)	Its binding to acetylcholine evokes mast cell degranulation.
	Chemokine receptors: CCR 1-3 and CXCR1-4	The CCR3 receptor has high affinity for eotaxin-1/CCL-11, eotaxin-2/CCL-24, and eotaxin-3/CCl-26 and mediates mast cell migration
	Endothelin receptor (ET_A,B)	Via this receptor, endothelin-1 determines mast cell degranulation and can induce the production of TNF-α and IL-6.
Activated complement receptors	C3aR	Activates mast cells, amplifying degranulation
Activated complement receptors	C5aR	Activates mast cells, amplifying degranulation
Maturation, differentiation, and activation receptor (type II receptor of tyrosine kinase)	c-Kit (CD117)	Its ligand targets Stem Cell Factor (SCF), for which it has high affinity (Kd −200 pM), causing receptor dimerization and phosphorylation of tyrosine residues. It is expressed in mast cells, hematopoietic and non-hematopoietic cells (such as melanocytes and interstitial cells of Cajal), and some tumors. In mast cells, it is expressed from their progenitors until their differentiation and maturation, and their development and survival depend on its activation by SCF, mediated intracellularly by the PI3K pathway, causing degranulation in response to allergens and cytokine production.
Neuropilin Receptors	Receptors NRP 1 and 2	Relevant in angiogenesis
Tyrosine kinase receptors for angiopoietin	Tie 1 and Tie 2	Its ligand is angiopoietin, which, together with VEGFs, is important for the proliferation, migration and survival of endothelial cells, including the formation of lymphatic vessels.
Neurokinin Receptor	NK1	This receptor is expressed when the mast cell is stimulated by IL4 or SCF.
Pattern Recognition Molecular Receptors (PAMPs and DAMPs)	TLR 1,2, 3,4, 5, 6,7, 8,9 e 10	Recognition of bacteria and fungi in particular, as well as peptides such as Gram-negative lipopolysaccharides (LPS), which can reach the bloodstream due to dysbiosis of the intestinal microbiome. Viral receptors (TLRs 3, 5, 7, and 9) are intracytoplasmic.
Major histocompatibility antigen	MHCII	HLA-DR
Sphingosine-1phosphate receptors	S1PR₂	Upregulates both allergen-induced degranulation and chemokine secretion
Glycosylphosphatidylinositol (GPI)-anchored cell surface receptor	CD48	Expressed on mast cells, eosinophils, and nearly all hematopoietic cells, including basophils, it is regulated by bacterial and viral products and immune-associated proteins. It is important as a costimulatory molecule in lymphocyte activation, facilitating cell adhesion and innate responses to bacteria (such as S. aureus and its exotoxins). Its soluble form (sCD48) is elevated in lymphoproliferative diseases, Sjögren's syndrome, and asthma compared to healthy individuals.
Receptors of Interleukins and Other Cytokines	IL-33	ST2 receptor: its ligand, IL-33, is a member of the IL-1 superfamily, initiating and amplifying the responses of type (2) innate lymphoid cells by stimulating the synthesis of IL-5 and IL-13 by these cells. IL-33 is also synthesized by mast cells after IgE-mediated activation and acts autocrinely on the mast cells themselves, stimulating them. IL-33 produced by the bronchial epithelium stimulates mast cells to produce IL-1β and IL-6, inducing the differentiation of Th0 lymphocytes into the Th17 phenotype after challenge with ovalbumin (OVA).
	IL-4	IL-4 Rα (type I) and IL-4Rα coupled to IL-13Rα2 (type II): when IL-4 binds to these receptors, it decreases mast cell proliferation, increases the expression of ICAM-1 (Intercellular Adhesion Molecule-1) and reduces the expression of c-Kit, but in synergy with SCF, IL-4 promotes mast cell proliferation and directs the production of cytokines in the IgE-dependent pattern.
	IL-5	IL-5Rα: activates mast cells, but is crucial for stimulating eosinophils, prolonging their survival, activation, adhesion to endothelial cells, differentiation and maturation, in addition to promoting the interaction between mast cells and eosinophils
	IL-6	IL6R: activated by IL-6, also synthesized by mast cells and innate immunity
	Vascular endothelial growth factor (VEGF) types 1 and 2	VEGF1R and VEGF2R: Mast cells can express receptors for VEGF, which they produce.
	Interferon gamma receptor	INFγ-Rα: INFgamma can determine mast cell apoptosis.
	Thymic Stromal Lymphopoietin (TSLP)	TSLPR: is a heterodimer composed of the α-chain and α-chain of IL-7R, and is the target of TSLP, produced primarily by epithelial and endothelial cells, which causes differentiation and proliferation of mast cells. It also induces the production of chemokines and the synthesis of Th2-type cytokines.
Prostaglandin D2 Receptor	CRTH2 or DP2	PGD2 is the main metabolite derived from arachidonic acid, released by IgE-activated mast cells. CRTH2 or DP2 is present intracellularly in mast cells and on the membranes of other cells such as LTh2, eosinophils, basophil macrophages, and dendritic cells. By binding to the PGD2 receptor, it mediates cell chemotaxis and promotes degranulation of mast cells, basophils, and eosinophils.
Costimulatory molecules	CD40L (CD154)	Transmembrane glycoprotein that binds CD40 on other immune cells, such as CD4+ T cells and platelets. The interaction between CD40L and CD40 on B cells is relevant for immunoglobulin class switching and memory B cell generation. Blocking the CD40L-CD40 interaction reduces the generation of regulatory T cells (Tregs). Activation of CD40 allows the expression of costimulatory molecules such as CD80 and CD86.
	OX40L (CD134L)	Involved in interaction with antigen-presenting cells (macrophages). Interacts with OX40 (CD134) of T lymphocytes, including promoting Th17-dependent inflammation, together with TNF-α and IL-6.
	OX40L (CD134L)	The interaction between OX40L and its ligand OX40 on T cells induces T cell expansion and proliferation and decreases the immunosuppressive effect of regulatory T cells (Treg)
Angiotensin-converting enzyme type 2 receptor	ACE2	Studies demonstrate its presence in mast cells of the respiratory tree.

Receptors and Type of Mediators	Name	Functions/Actions
Cannabinoids	CB1	Under the action of endocannabinoids (anandamide and 2-arachidonoylglycerol), it promotes regulatory actions. In mast cells, it has anti-inflammatory effects, with CB1 suppressing mast cell degranulation by increasing cytosolic cAMP levels.
Cannabinoids	CB2	Under the action of endocannabinoids (anandamide and 2-arachidonoylglycerol), it promotes regulatory actions. In mast cells, it has anti-inflammatory effects by suppressing the release of pro-inflammatory mediators.
Sphingosine-1phosphate receptors	S1PR₁	Its activation by agonists decreases allergic inflammation in the airways and reduces the accumulation of eosinophils and T cells
Immunoglobulins	FcγRIIb (low-affinity receptor for IgG type b) (expressed only in mice, but not in human mast cells)	In murine mast cells, FcγRIIb can cross-link adjacent FcɛRI on the cell membrane with the same multivalent ligand and form an immune complex and inhibit FcɛRI-dependent mast cell activation, preventing degranulation and synthesis of newly formed mediators.
CD300 Family	CD300a	Its ligands are phosphatidylserine and phosphatidylethanolamine (expressed in the early stages of apoptosis/cell death) as membrane signals for phagocytosis. In the intracellular space, its action activates the SHP-1 protein, dephosphorylates SYK, and decreases intracellular calcium influx. CD300a expression on mast cells can be inhibited by eosinophil major basic protein (MBP) and eosinophil-derived neurotoxins.
Siglecs Family (sialic acid-binding immunoglobulin-like lectins)	Siglec-6	Its activation prevents mast cell activation.
	Siglec-7	Its activation results in inhibition of mediator release via FcɛRI-dependent pathway, by cross-linking with adjacent FcɛRI on the cell membrane.
	Siglec-8	Stimulated by IL-5, IL-33, or GM-CSF, mast cell apoptosis is induced. Activation of mast cell mediators results in FcɛRI-dependent inhibition of mast cell mediator release.
Leukocyte Ig-like receptor (LIR)	Inhibitory receptors LIR-1, LIR-2 and LIR-3	LIR-1 is expressed in mature mast cells and LIR2 and LIR-3 in mast cell progenitors. They promote inhibition of mast cell activity.
Membrane glycoprotein receptor belonging to the SIRP family	SIRP-α	Its activation inhibits FcɛRI-mediated mast cell activation in mice
CD200R	CD200R	Its activation inhibits FcɛRI-mediated mast cell activation
c-lectin mast cell function-associated antigen (a variant of lectin-like type II transmembranal glycoprotein)	MAFA	Inhibits degranulation and cytokine release by IgE-activated mast cells in rat mucosa
Platelet-Endothelial Cell Adhesion Molecule-1	PECAM-1	Its activation inhibits FcɛRI-mediated mast cell activation
Leukocyte-associated I-like receptor (LAIR)	LAIR-1	Its activation results in the reduction of preformed mediators and the release of cytokines. Its ligand is collagen.
Prostanoid-E Receptors	EP2 e EP4	Prostaglandin E2 (PGE2) binds to the EP2 receptor and inhibits mast cell degranulation, cytokine transcription, and eicosanoid production via stimulation of FcɛRI. Binding to EP4 inhibits mast cell activation. One of the mechanisms of urticaria caused by nonsteroidal anti-inflammatory drugs is the decrease in PGE2 synthesis and loss of its mast cell-silencing mechanisms.
Programmed death receptor	PDL1	Induces mast cell apoptosis

Receptors and Type of Mediators		Name	Functions/Actions
Preformed (generally stored in granules of 0.2 to 0.8 μm in diameter, of skin mast cells. TC mast cells, chymase-tryptase positive)	Amines	Histamine	Vasodilation, expression of VCAM in the vascular endothelium activating endothelial cells, increased capillary permeability, stimulation of pruritus
	Amines	Polyamines	Vasodilation
	Proteoglycans	Heparin	Anticoagulation
		Chondroitin sulfate	Inhibits the activation of other connective tissue mast cells
		Serglycin	Proteoglycan to which heparin binds and whose function is to maintain the homeostasis of mast cell granules to be secreted.
	Proteases	Tryptases (expressed only in mast cells)	Tryptase-α, Tryptase-βI Tryptase-βII, Tryptase-βIII, Tryptase-γ, Tryptase-δ: Increased capillary permeability, stimulation of pruritus via PAR2
		Chymase-1 (expressed only in skin mast cells)	Protease stored in skin mast cell granules, promoting inflammation and tissue destruction
		Cathepsin G
		Carboxypeptidase A
		Granzyme B 3
	Lysosomal enzymes	β-glucoronidase	Glycosidase that participates in the catabolism of mucopolysaccharides
		β-Hexosaminidase	Involved in hydrolysis mechanisms.
		Arylsulfatase	Catalyzes reactions of sulfonated hexoses.
	Cytokines	TNF-α	Stimulates TH1 polarization
		bFGF	Stimulation of fibroblasts in the regeneration of the intercellular matrix
		IL-4	Stimulates type 2 inflammation
		SCF	Maturation, differentiation and increased survival of mast cells
		VEGFb	Increased capillary permeability and angiogenesis
Neoformed (synthesized minutes to hours after mast cell stimulation)	Lipids	Prostaglandin D2 (PGD2)	Vasodilation and increased capillary permeability
			Recruitment and activation of Th2 lymphocytes
			Chemotaxis and activation of basophils and eosinophils
			Migration of type 2 innate immune lymphoid cells (ILC2)
		Leukotriene B4 (LTB4)	Chemotaxis of neutrophils, mast cells, and dendritic cells
		Leukotriene B4 (LTB4)	Recruitment of CD8+ lymphocytes
		Leukotriene C4 (LTC4)	Eosinophil migration
		Leukotriene D4 (LTD4)	Migration of eosinophils and neutrophils
		Leukotriene E4 (LTD4)	Migration of eosinophils and ILC2
		Prostaglandin E2 (PGE2)	Stabilization of mast cells and their decreased activation and migration of dendritic cells
		Platelet activating factor (PAF)	Vasodilation, increased capillary permeability, increases adhesion of blood cells to the vascular endothelium and promotes migration to the extravascular space
	Cytokines	Interleukin-1 (IL-1) (increased serum expression in CSU)	Recruitment of eosinophils, neutrophils, migration of dendritic cells, activation of the inflammasome; IL-1β determines plasma extravasation from vessels
		Interferon type I (INF-α and INF-β) and II (INF-γ and has decreased serum expression in CSU)	Secreted in viral infections such as respiratory syncytial virus. It leads to the aggregation of lymphocytes, eosinophils, mast cells, macrophages, and neutrophils.
		IL-2 (increased serum expression in CSU)	Proliferation of effector T lymphocytes and B lymphocytes; development of Treg cells; growth factor for B lymphocytes and stimulation of antibody synthesis
		IL-3 (increased expression in CSU lesions)	Activation of eosinophils and basophils; enhancement of FcεRI expression in basophils and stimulation of their longer survival
		IL-4 (increased serum expression in CSU)	Activation of T lymphocytes and basophils; increased humoral immunity; recruitment of eosinophils; differentiation from Th0 to Th2 with induction of type 2 inflammatory response and monocytes; differentiation into M2 macrophages; factor of increased survival for T and B lymphocytes; promotes immunoglobulin class switching, determining the production of IgE and IgG1 by B lymphocytes.
		IL-5 (increased serum expression in CSU)	Increase in the number of eosinophils due to increased adhesion and chemotaxis capacity to the skin.
		IL-6 (increased serum expression in CSU)	Differentiation of B lymphocytes and subsequent production of IgG, IgM and IgA; increased mast cell proliferation, maturation and reactivity (priming)
		IL-8 (increased serum expression in CSU)	Acts as a chemoattractant for T lymphocytes, basophils, eosinophils, NK cells, and neutrophils
		IL-9 (increased serum expression in CSU)	Acts as a growth factor for mast cells and T lymphocytes; inhibits Th1-type cytokines and promotes the proliferation of CD8+ lymphocytes and mast cells
		IL-10 (increased serum expression in CSU)	Inhibits Th1 and Tc1 cell function; activates B lymphocytes and induces autoantibody production by B cells
		IL-12	Recruitment of CD8+ T lymphocytes; induction of Th1 lymphocyte responses
		IL-13 (increased serum expression in CSU)	Activation of mast cells and eosinophils; increased eosinophil survival
		IL-16	T lymphocyte recruitment and dendritic cell migration
		IL-17A (increased serum expression in CSU)	Induction of pro-inflammatory cytokines and chemokines, with recruitment of neutrophils
		IL-18	Dendritic cell migration
		IL-25 (increased expression in CSU lesions)	Induction of Th2 responses and inhibition of Th1 and Th17 responses; induction of the production of IgE and IgG1, IL-4, IL-5, IL-9 and IL-13
		IL-31 (increased serum expression in CSU)	Induction of IL-6 and IL-8, CXCL1, CXCL8, CCL2 and CCL8 in eosinophils
		IL-33 (increased serum expression in CSU)	Increases allergic stimulation of mast cells and basophils; induces IL-31 production in mast cells; increases integrin expression in basophils and eosinophils, leading them to the skin; promotes mast cell maturation
		TNF-α ( “de novo” synthesis: increased serum expression in CSU)	Promotes activation of endothelial cells, proliferation of effector T lymphocytes, increases the expression of ICAM-1 in eosinophils allowing them to migrate to the skin; activation of monocytes and macrophages, recruitment of neutrophils and proliferation of T lymphocytes
		GM-CSF	Determines migration of dendritic cells to lymph nodes
	Chemokines	CCL1	Recruitment of T cells and monocytes
		CCL2	Recruitment of T cells, monocytes, and neutrophil migration
		CCL3	Recruitment of T cells and monocytes
		CCL4	Recruitment of T cells and monocytes
		CCL5	Recruitment of CD8+ T cells, monocytes, basophils, eosinophils, NK cells and dendritic cells
		CCL7	Recruitment of T cells: monocytes, basophils, eosinophils, NK cells, immature dendritic cells, and hematopoietic progenitor cells
		CCL18	Recruitment of naive T cells, CD4+ and CD8+ T lymphocytes, memory T lymphocytes, B lymphocytes, and immature dendritic cells
		CCL20	Recruitment of B lymphocytes, memory effector T lymphocytes, recruitment of CD11b+ dendritic cells
		CXCL1	Neutrophil recruitment
		CXCL2	Recruitment of neutrophils, basophils, and eosinophils
		CXCL3	Neutrophil recruitment
		CXCL8	Recruitment of neutrophils and CD4+ T lymphocytes
		XCL1	Dendritic cell migration and antigen cross-presentation
		CXCCL1	Recruitment of monocytes and T lymphocytes and increased survival

Clinical aspects	Hematological and/or serological aspects
• Older age at disease onset	• Low eosinophil count (<0.05 × 109/L)
• Female sex	• Low basophil count (<0.01 × 109/L)
• Presence of angioedema	• Low serum vitamin D levels
• Poor response to antihistamines	• Elevated CD2023c expression on basophils
• Positive autologous serum test	• Elevated eotaxin levels
• Hypersensitivity to nonsteroidal anti-inflammatory drugs (NSAIDs)	• Elevated VEGF levels
• Long-lasting CSU	• Elevated MMP-9 levels
	• Elevated IL-6 levels
	• Elevated IL-18 levels
	• Elevated IL-33 levels
	• Elevated C-reactive protein (CRP)
	• Elevated D-dimers (in half of patients with severe disease)
	• Elevated antithyroid antibodies (anti-TPO ≥ 34 kU/L)
	• Elevated mean platelet volume
	• Elevated erythrocyte sedimentation rate (ESR)
	• Positive basophil activation test (BAT)
	• Elevated serum adenosine levels
	• Elevated transglutaminase 2 activity

	CSU	AIS	Schnitzler	NUD/NUSI	UV	UD	Drug	AIBD	Wells	AOSD
Laboratory alterations	None relevant	Elevated CRP, ESR, leukocytosis, neutrophilia, lymphopenia in some cases, elevated serum protein amyloid	Leukocytosis, neutrophilia, elevated CRP/ESR, IgM or IgA monoclonal gammopathy. Normal or elevated serum complement	Leukocytosis, neutrophilia, elevated CRP and ESR	May have complement consumption (↓C3 and/or ↓C4). In case of hypocomplementemia, it may present with cytopenias, ANA+, in addition to glomerulonephritis and COPD.	None relevant	Uncommon, possibly eosinophilia.	Eosinophilia, D-Dimer, and elevated total serum IgE in bullous pemphigoid. IgA antitransglutaminase antibodies in dermatitis herpetiformis.	Eosinophilia may occur.	Leukocytosis with neutrophilia, anemia, very high ferritin levels, elevated ceruloplasmin, elevated ESR and CRP during disease activity, as well as elevated AST and ALT and LDH, in addition to polyclonal gammopathy.
Systemic manifestations	Uncommon	Fever, arthralgias, arthritis, general malaise, visceromegaly	Arthralgia, osteosclerosis in the femur and tibia, then humerus, radius, ulna and fibula, lymphadenopathy, possibly visceromegaly	Fever, myalgia and fatigue, less frequently chest or abdominal pain.	In the hypocomplementemic form arthritis, uveitis, myalgias, serositis.	Usually absent or uncommon	Uncommon, except in serum sickness with urticarial manifestations, arthralgia, fever, and myalgia.	Uncommon	Rare.	Lymphadenopathy, sore throat, pretibial pain, visceromegaly, evening fever.
Angioedema	40‒60% of patients	Very rare	Rare	Absent	May be present	Absent	Uncommon, except in serum sickness	Absent.	Rare.	Absent in general.
Residual hyperpigmentation/desquamation	No	It may occur eventually	Possible	Absent	May be present along with purpura	Fine, light desquamation may occur.	Rare.	It may occur	It may occur	It may occur
Associated symptoms	Intense pruritus	No or minimal pruritus. Burning sensation may occur.	Pruritus is almost absent, or absent.	Absent or minimal pruritus.	Burning sensation and pain prevail over pruritus.	Intense pruritus	Pruritus	Intense pruritus	Burning sensation and pruritus.	Minimal or absent pruritus.
Distribution of lesions	Bilateral and asymmetric, in any area	Bilateral, usually symmetrical, in the trunk and extremities.	Asymmetrical, especially trunk and limbs.	Asymmetrical, trunk and limbs in particular.	Asymmetrical and all skin.	Bilateral, somewhat symmetrical, especially in the trunk and proximal limbs.	Bilateral and symmetrical, possibly in large folds	Generally symmetrical, varying with the bullous autoimmune disease in question.	Trunk and limbs.	Face, trunk and limbs.
Types of lesions	Hives and/or angioedema.	Nearly flat hives to infiltrated plaque lesions.	Urticated plaques and nearly flat urticarial lesions.	Macular erythema and/or palpable rash that resolves without sequelae and may be urticarial in nature.	Urticarial lesions that persist for more than 24 hours in the same location. Purpura and hyperpigmentation may be observed.	Pink, erythematous hives, slightly elevated, some with signs of mild lichenification. Excoriations are common.	Urticarial lesions sometimes associated with eczematous eruptions.	Urticarial lesions, possibly vesicles and/or erosions.	Hives with an arcuate or annular appearance. Occasional edematous-vesicular, papular lesions, and infiltrated plaques.	Urticarial lesions, slightly raised and persistent linear lesions, resembling dermographism.
Duration of lesions	Minutes or up to 24 hours	12 hours or a few days	>24 hours in the same place.	<24 hours	Two days to weeks in the same place	>24 hours and sometimes several days in the same place.	>24 hours	Several days or weeks in the same places.	>24 hours and sometimes several days in the same place.	>24 hours.
Histopathology	Nonspecific. Edema with Perivascular infiltrate of lymphocytes and polymorphonuclear cells. No epidermal changes.	There may be neutrophilic perivascular infiltrate and neutrophilic epidermotropism	There may be neutrophilic perivascular infiltrate and neutrophilic epidermotropism (epidermis, hair follicles, and eccrine glands)	Neutrophilic infiltration in the interstitium, between the collagen fibers, sometimes with a “single-file” appearance; without leukocytoclasis or vasculitis. No edema, and neutrophilic epidermotropism may be present.	Angiocentric infiltrate with or without interstitial spread. Leukocytoclasis and transmural polymorphonuclear cell infiltrate. Fibrin deposits in the blood vessel, red blood cell extravasation, and foci of thrombosis.	Mild spongiosis, perivascular infiltrate of lymphocytes and eosinophils, which may be in the superficial and middle dermis, is often mistaken for a drug reaction	Variable, with spongiosis, parakeratosis, vacuolar degeneration of the basal layer in the epidermis, keratinocyte apoptosis, perivascular inflammatory infiltrate of lymphocytes, eosinophils and/or neutrophils.	In lesions that are macroscopically free of vesicles or blisters in bullous pemphigoid, there may be eosinophilic spongiosis and eosinophils in the superficial dermis; in dermatitis herpetiformis, there may be neutrophils in the papillary dermis.	Discreet edema in the dermis with abundant eosinophils and “flame or blaze” figures, which are not pathognomonic of the disease.	Perivascular lymphomononuclear infiltrate with neutrophils and fewer eosinophils. Neutrophilic epidermotropism may be present.

Chronic spontaneous urticaria: update on pathogenesis and therapeutic implications

Abstract