Urticaria

Background

Urticaria is a very common dermatologic condition.

The current clinical classification of urticaria and angioedema is outlined below. (Adapted from Grattan CE, etal. J Am Acad Dermatol 2002;46:645-657)

Ordinary urticaria Recurrent or episodic urticaria not in the categories below

Physical urticaria
(defined by the triggering stimulus) Adrenergic urticaria
Aquagenic urticaria
Cholinergic urticaria
Cold urticaria
Delayed pressure urticaria
Dermographism
Exercise-induced anaphylaxis
Localized heat urticaria
Solar urticaria
Vibratory angioedema

Contact urticaria Induced by biologic or chemical skin contact

Urticarial vasculitis Defined by vasculitis as shown by skin biopsy specimen

Angioedema Without wheals

OUTLINE

Disease Associations

Pathogenesis

Laboratory/Radiologic/Other Diagnostic Testing

Gross Appearance and Clinical Variants

Histopathological Features and Variants

Prognosis and Treatment

Commonly Used Terms

Internet Links

DISEASE ASSOCIATIONS CHARACTERIZATION

DRUGS

Drug-induced urticaria and angioedema: pathomechanisms and frequencies in a developing country and in developed countries.

Greaves MW, Hussein SH.

Department of Dermatology, Hospital Kuala Lumpur, Malaysia.
Int Arch Allergy Immunol 2002 May;128(1):1-7 Abstract quote
A careful drug history should be obtained from all patients with acute or chronic urticaria/angioedema, especially in the elderly. Although strictly comparable data are lacking, drug-induced urticaria appears to be more common in developed countries than in Malaysia, at least in a Hospital setting. Culprit drugs include antibiotics, analgesics and contrast media.

Pseudoallergic drug-induced urticaria mimicks true allergic urticaria, but without an evident immunological basis, and is at least as common as the allergic type. In Malaysia, and in many other countries compulsory, ingredient labelling of 'traditional' medicines would do much to reduce the frequency of drug-induced urticaria.

LACTOSE INTOLERANCE

Familial aquagenic urticaria associated with familial lactose intolerance.

Treudler R, Tebbe B, Steinhoff M, Orfanos CE.

Department of Dermatology, University Medical Centre Benjamin Franklin, The Free University of Berlin, Germany.
J Am Acad Dermatol 2002 Oct;47(4):611-3 Abstract quote
Aquagenic urticaria is a rare disorder characterized by the occurrence of pruritus and wheals after temporary contact with water.

The familial occurrence of aquagenic urticaria over 3 generations is reported here in association with familial lactose intolerance, a condition in which the enzyme lactase encoded on chromosome 2, is deficient. In two patients, a young man and his mother, we verified the appearance of pruritic hives 5 to 10 minutes after contact with water of any temperature. Other types of physical urticaria were absent, and mastocytosis was excluded by extensive laboratory investigations; lactose intolerance was confirmed in both patients by H(2)-exhalation test. In these patients the clinical symptoms did not respond to antihistamines or UV-radiation therapy.

Four other members of the family had wheals from water contact, two of whom had lactose intolerance. Two other members had lactose intolerance only.

Although the association of aquagenic urticaria with lactose intolerance may be coincidental, attention is drawn to the fact that the 2 conditions, known to be familial, may coexist in the same family, possibly based on an association of gene loci.

MYCOSIS FUNGOIDES

Cold urticaria in a patient with mycosis fungoides.

Koay J, Jones D, Duvic M.

Baylor College of Medicine, Houston, Texas 77030, USA.
J Am Acad Dermatol 2002 Oct;47(4):608-10 Abstract quote
We report what we believe to be the first documentation of a patient with both cold urticaria and mycosis fungoides. The patient described a marked worsening of his long-standing lesions of mycosis fungoides at the same time as the onset of cold sensitivity.

We believe this suggests a possible association between these 2 rare diseases.

PATHOGENESIS CHARACTERIZATION

GENERAL

The pathogenesis of chronic idiopathic urticaria.

Sabroe RA, Greaves MW.

St John's Institute of Dermatology, St Thomas' Hospital, London, England.
Arch Dermatol 1997 Aug;133(8):1003-8 Abstract quote
Chronic idiopathic urticaria (CIU) can be extremely disabling and difficult to treat, with little response to antihistamine therapy.

The pathogenic mechanisms of the disease are not well understood, but the primary effector cell is the mast cell. Release of mast cell mediators can cause inflammation and accumulation and activation of other cells, including eosinophils, neutrophils, and possibly basophils.

Recent work has demonstrated that about one third of patients with CIU have circulating functional histamine-releasing autoantibodies that bind to the high-affinity IgE receptor (Fc epsilon RI) or, less commonly, to IgE; mast cell-specific histamine-releasing activity that has not yet been fully characterized; no identifiable circulating histamine-releasing activity.

The mainstay of treatment of CIU consists of antithistamines, but immunotherapy using plasmapheresis, intravenous immunoglobulin, and cyclosporin may be valuable in severely affected patients with treatment-resistant disease. The response to immunomodulation and the recent finding of an association with HLA DR4 lend further support for an autoimmune basis to CIU in some patients.

AUTOANTIBODIES

Autoantibodies against the high-affinity IgE receptor as a cause of histamine release in chronic urticaria.

Hide M, Francis DM, Grattan CE, Hakimi J, Kochan JP, Greaves MW.

St. John's Institute of Dermatology, United Medical School, Guy's Hospital, London, United Kingdom.
N Engl J Med 1993 Jun 3;328(22):1599-604 Abstract quote
BACKGROUND. Most urticarias are induced by vasoactive mediators such as histamine released from mast cells. Although mast cells are activated by allergens through cross-linking of cell-surface--bound IgE, this mechanism does not appear to explain most cases of chronic urticaria, which, when allergic, infectious, drug-induced, or physical causes cannot be identified, are classified as idiopathic.

METHODS. We recruited 26 patients with chronic idiopathic urticaria, in whom intradermal injection of autologous serum caused a wheal-and-flare response. Serum from four patients that induced marked histamine release from basophils from a donor with very low serum IgE levels was studied with respect to the IgE dependence of the histamine release, the activity of the IgG fractions, and the neutralizing effect of a recombinant preparation of the soluble extracellular domain of the alpha subunit of the high-affinity IgE receptor (sFc epsilon RI alpha).

RESULTS. The histamine-releasing activity of the serum was abolished by passive sensitization of basophils with myeloma IgE, enhanced after dissociation of IgE by treatment with lactic acid, and induced by IgG fractions from the serum of all four patients. Preincubation of the serum and isolated IgG with sFc epsilon RI alpha resulted in almost complete neutralization.

CONCLUSIONS. Histamine-releasing IgG autoantibodies against the alpha subunit of the high-affinity IgE receptor are present in the circulation of some patients with chronic urticaria. Autoantibody-induced cross-linking of IgE receptors may be an important mechanism in the pathogenesis of chronic urticaria and other diseases mediated by mast cells.

CHROMOSOMAL ABNORMALITIES

New Mutations of CIAS1 That Are Responsible for Muckle-Wells Syndrome and Familial Cold Urticaria: A Novel Mutation Underlies Both Syndromes.

Dode C, Le Du N, Cuisset L, Letourneur F, Berthelot JM, Vaudour G, Meyrier A, Watts RA, Scott DG, Nicholls A, Granel B, Frances C, Garcier F, Edery P, Boulinguez S, Domergues JP, Delpech M, Grateau G.

INSERM EMI 00-05, Institut Cochin, Hopital Cochin, Universite Paris V, Paris, France.
Am J Hum Genet 2002 Jun;70(6):1498-506 Abstract quote
Mutations of CIAS1 have recently been shown to underlie familial cold urticaria (FCU) and Muckle-Wells syndrome (MWS), in three families and one family, respectively. These rare autosomal dominant diseases are both characterized by recurrent inflammatory crises that start in childhood and that are generally associated with fever, arthralgia, and urticaria. The presence of sensorineural deafness that occurs later in life is characteristic of MWS. Amyloidosis of the amyloidosis-associated type is the main complication of MWS and is sometimes associated with FCU. In FCU, cold exposure is the triggering factor of the inflammatory crisis.

We identified CIAS1 mutations, all located in exon 3, in nine unrelated families with MWS and in three unrelated families with FCU, originating from France, England, and Algeria. Five mutations-namely, R260W, D303N, T348M, A439T, and G569R-were novel. The R260W mutation was identified in two families with MWS and in two families with FCU, of different ethnic origins, thereby demonstrating that a single CIAS1 mutation may cause both syndromes. This result indicates that modifier genes are involved in determining either a MWS or a FCU phenotype.

The finding of the G569R mutation in an asymptomatic individual further emphasizes the importance of such modifier a gene (or genes) in determining the disease phenotype. Identification of this gene (or these genes) is likely to have significant therapeutic implications for these severe diseases.

CYTOKINES

Upregulation of TNF-alpha and IL-3 expression in lesional and uninvolved skin in different types of urticaria.

Hermes B, Prochazka AK, Haas N, Jurgovsky K, Sticherling M, Henz BM.

Neukolln Hospital, Berlin, Germany.

J Allergy Clin Immunol 1999 Feb;103(2 Pt 1):307-14 Abstract quote
BACKGROUND: Although mast cells are known to secrete a broad spectrum of proinflammatory and immunomodulatory cytokines, the role of these molecules in mast cell-dependent cutaneous inflammation is not clear.

OBJECTIVE: We decided to study biopsy specimens from lesional and nonlesional skin of patients with acute, chronic recurrent, delayed pressure, and cold urticaria; from fleeting wheals of prick test reactions to allergens; and from normal skin of nonallergic subjects.

METHODS: Cryostat sections were stained by immunohistochemistry with antibodies against IL-3, IL-8, TNF-alpha, and mast cell-specific tryptase. In serial sections with tryptase and each cytokine, reactivity of mast cells was studied as well.

RESULTS: Compared with normal skin and prick test reactions, immunoreactivity for TNF-alpha and IL-3 was significantly increased on endothelial and perivascular cells of the upper dermis in all urticaria lesions. In nonlesional skin comparable upregulation was noted on endothelial cells and for TNF-alpha on perivascular cells of patients with delayed pressure urticaria. In addition, TNF-alpha was expressed throughout the epidermis in lesional and nonlesional skin of patients with all types of urticaria, but not in normal control subjects. Sequential biopsy specimens from patients with cold urticaria showed upregulation of TNF-alpha and IL-3 on endothelial cells 30 minutes after elicitation of lesions with an ice cube. In contrast to these findings, epidermal immunoreactivity, as well as endothelial and perivascular cell expression of IL-8, were only slightly altered in urticaria compared with normal skin. In sequentially stained sections, few tryptase-positive mast cells reacted to TNF-alpha, few reacted to IL-3 in pressure urticaria only, and practically none stained for IL-8.

CONCLUSION: These findings suggest that the cytokines studied here are involved in the pathology of urticaria, possibly by inducing subthreshold inflammation in endothelial cells of uninvolved skin.

Immune profiles of patients with chronic idiopathic urticaria.

Piconi S, Trabattoni D, Iemoli E, Fusi ML, Villa ML, Milazzo F, Clerici M.

First Department of Infectious Disease and Allergy Unit, L. Sacco Hospital, Milan, Italy
Int Arch Allergy Immunol 2002 May;128(1):59-66 Abstract quote
Background: The immunologic characterization of chronic idiopathic urticaria (CIU) is still incomplete. In particular, it is not known if positivity to the intradermal autologous serum skin test (ASST) identifies an immunologic subset of CIU patients.

Methods: Nineteen CIU patients and 15 healthy controls were enrolled in the study. A diagnostic flowchart was designed to select CIU patients, who were then analyzed by ASST. Cytokine and chemokine production and the expression of adhesion molecules was measured in patients and controls.

Results: In CIU patients compared to controls, it was found that (1) TNF-alpha, IL-10, MIP-1alpha and RANTES production was augmented and IL-2 and INF-gamma reduced, and (2) CD44, CD11a and CD62L expression on CD4 and CD8 cells was augmented. Additionally, TNF-alpha and chemokine production was significantly increased in CIU patients with a negative ASST (p-; n = 10) compared to patients with a positive response to the test.

Conclusions: The presence of an inflammatory process in CIU patients is suggested by the findings that the production of both TNF-alpha and chemokines as well as the expression of adhesion molecules is increased in these patients. Similarly to what is seen in rheumatoid arthritis, augmented IL-10 production might be secondary to the attempt to hamper the inflammatory milieu. Immune profiles are particularly altered in CIU p- patients, in whom a more aggressive therapeutic strategy might be considered.

MAST CELLS

Mast cell number and phenotype in chronic idiopathic urticaria.

Smith CH, Kepley C, Schwartz LB, Lee TH.

Department of Allergy & Respiratory Medicine, United Medical School, Guy's Hospital, London, England.
J Allergy Clin Immunol 1995 Sep;96(3):360-4 Abstract quote
BACKGROUND: Increased levels of histamine have been previously demonstrated in patients with chronic idiopathic urticaria.

OBJECTIVE: The purpose of the study was to determine whether increased numbers of mast cells are present in lesional skin from such patients.

METHODS: Mast cells have been quantified in lesional (n = 11) and nonlesional (n = 9) skin from patients with chronic idiopathic urticaria and compared with site-matched skin from healthy control subjects (n = 10). Mast cells were identified by using a sensitive, double-labeling immunohistochemical technique with specific monoclonal antibodies to mast cell tryptase and chymase and quantified under light microscopy.

RESULTS: No significant differences in mast cell numbers from lesional, nonlesional, or control skin were observed (p > 0.1, Student's t test). In both patients with urticaria and control subjects, more than 99% of cutaneous mast cells contained tryptase and chymase.

CONCLUSIONS: These data indicate that increased skin histamine in chronic idiopathic urticaria is not caused by increased mast cells and may alternatively reflect an increase in histamine content per mast cell, enhanced mast cell activation, or recruitment of basophils into skin in patients with chronic idiopathic urticaria

LABORATORY/RADIOLOGIC/
OTHER TESTS
CHARACTERIZATION

RADIOLOGIC

LABORATORY MARKERS

Preliminary identification of a low molecular weight serological mediator in chronic idiopathic urticaria.

Grattan CE, Hamon CG, Cowan MA, Leeming RJ.

Department of Dermatology, General Hospital, Birmingham, U.K.
Br J Dermatol 1988 Aug;119(2):179-83 Abstract quote
Sixteen patients with chronic idiopathic urticaria were skin tested with their own serum, IO with autologous plasma and five with serum that had been heated to 56 degrees C to inactivate complement.

Eight showed a weal and flare response to whole serum, four to plasma and five to heat-treated serum. All serum-positive patients showed the same response to their own plasma and to heated serum, indicating that the mediator concerned is not generated by clotting and is not dependent on a functioning complement pathway.

Three control subjects were negative to autologous serum, plasma and heated serum. Local tachyphylaxis was demonstrated in five serum-positive patients on reinjection of the same site with autologous serum on 3 consecutive days. This raises the possibility that the serological mediator may be acting by mast cell degranulation or directly on receptors in blood vessels and that repeated injections could induce a change in the number of receptors. Passage of whole autologous serum from four serum-positive patients through ultrafiltration membranes showed that fractions with a molecular weight of less than 30,000 daltons were still able to produce a positive skin test response, but those less than 1000 daltons were not. All serum fractions from two serum-negative patients and three normal controls were negative.

Whole autologous serum from five serum-positive patients and two control subjects were separated by column chromatography. On skin testing with pooled fractions, the greatest response was produced by fractions of 10,000-15,000 daltons in the serum-positive patients, but there was no response in the controls.

GROSS APPEARANCE/
CLINICAL VARIANTS CHARACTERIZATION

GENERAL

The effectiveness of a history-based diagnostic approach in chronic urticaria and angioedema.

Kozel MM, Mekkes JR, Bossuyt PM, Bos JD.

Department of Dermatology, University of Amsterdam, The Netherlands.
Arch Dermatol 1998 Dec;134(12):1575-80 Abstrac
OBJECTIVE: To assess the value of extensive laboratory screening for the identification of causes in patients with chronic urticaria and/or angioedema.

DESIGN: In a prospective study involving 220 patients, 2 diagnostic strategies were compared: the combination of detailed history taking and limited laboratory investigations vs detailed history taking and extensive laboratory screening. The results of the extensive screening program were initially kept secret from the patients and the physicians. Later, all results were disclosed, and an investigation was undertaken to find out whether this information changed the initial diagnosis. The patients were followed up for 1 year to evaluate the results of interventions and to detect latent causes.

SETTING: The study was performed in the outpatient department of a secondary and tertiary care center with institutional practice.

PATIENTS: A total of 238 consecutive new patients with chronic urticaria and/or angioedema edema were referred; 18 of them refused participation. One patient was unavailable for follow-up.

MAIN OUTCOME MEASURE: The difference in the number of identified causes between both approaches and the nature of the causes that would have been missed by omitting extensive laboratory screening.

RESULTS: With a questionnaire and the limited laboratory tests, a cause was found in 45.9% of the patients, compared with 52.7% with the questionnaire and the extended screening program. Except for one parasitic infection, missed diagnoses were mainly adverse reactions to drugs or food detected by standard elimination procedures, not by laboratory investigations.

CONCLUSION: Routine laboratory screening did not contribute substantially to the diagnosis of chronic urticaria or to the detection of underlying disorders.

Chronic urticaria.

Grattan CE, Sabroe RA, Greaves MW.

Dermatology Centre, Norfolk and Norwich University Hospital, Norwich; and St John's Institute of Dermatology, St Thomas' Hospital, London.

J Am Acad Dermatol 2002 May;46(5 Pt 1):645-57 Abstract quote
Chronic urticaria has a spectrum of clinical presentations and causes. About 50% of patients with "idiopathic" disease have histamine-releasing autoantibodies in their blood. The term autoimmune urticaria is increasingly being accepted for this subgroup of patients, in whom immunosuppressive therapies may be appropriate if conventional approaches to management are unsuccessful.

This article reviews the classification, causes, and management of chronic urticaria in light of recent advances in the understanding of its etiology.

VARIANTS

EXERCISE INDUCED

Exercise-induced urticaria and anaphylaxis.

Volcheck GW, Li JT.

Division of Allergy and Outpatient Infectious Diseases and Internal Medicine, Mayo Clinic Rochester, Minnesota 55905, USA.
Mayo Clin Proc 1997 Feb;72(2):140-7 Abstract quote
Exercise-induced urticaria and anaphylaxis have become increasingly recognized during the past 2 decades as more people participate in physical activities.

These syndromes can be categorized as cholinergic urticaria or exercise-induced anaphylaxis based on the clinical manifestation. Newer subsets such as food-dependent and familial exercise-induced anaphylaxis have also been recognized. Further studies are needed to characterize the variables involved in mast cell activation and mast cell mediator release in these syndromes. The management strategy for patients who have exercise-induced syndromes with skin manifestations only differs from the management for those with systemic symptoms.

Currently, antihistamines, as a single agent or in combination with other agents, may be helpful prophylactically in both groups. Avoidance of precipitating factors, modification of exercise, and use of a self-injectable epinephrine kit are recommended for patients with anaphylaxis.

HEREDITARY ANGIOEDEMA

Detection of C1 inhibitor mutations in patients with hereditary angioedema.

Zuraw BL, Herschbach J.

Department of Molecular Medicine, The Scripps Research Institute, La Jolla, USA.
J Allergy Clin Immunol 2000 Mar;105(3):541-6 Abstract quote
BACKGROUND: Hereditary angioedema (HAE) results from a deficiency in the functional level of C1 inhibitor caused by mutations in the C1 inhibitor gene. The mutations responsible for HAE have been shown to be heterogeneous.

OBJECTIVE: Because the identification of C1 inhibitor mutations may depend, in part, on the technique used to screen for mutations, we screened the entire C1 inhibitor coding region to identify mutations in a cohort of patients with HAE.

METHODS: By using single-stranded conformational polymorphism analysis, 24 subjects with HAE from 16 different kindreds were screened for C1 inhibitor polymorphisms. C1 inhibitor mutations were identified by sequencing the exons containing identified polymorphisms.

RESULTS: All 24 subjects with HAE had identifiable polymorphisms, involving exons 2, 3, 4, 5, or 8. Fourteen different C1 inhibitor mutations were identified: 8 missense, 1 nonsense, 4 frameshift, and 1 small deletion mutations. No large deletions or duplications were found. Nine of the 14 mutations represent newly recognized C1 inhibitor mutations, 6 of which involve exon 4.

CONCLUSIONS: Single-stranded conformational polymorphism is an effective approach for identifying new mutations in HAE. Elucidation of the range of C1 inhibitor mutations causing HAE is important for both defining which residues are required for C1 inhibitor secretion or function and providing the basis for future studies to define the relationship between the C1 inhibitor genotype and disease severity.

Hereditary angioedema. Long-term follow-up of 88 patients. Experience of the Argentine Allergy and Immunology Institute.

Fabiani JE, Avigliano A, Dupont JC, Fabiana JE.

Instituto Argentino de Alergia e Inmunologia Potosi 3880 (1199) Capital Federal, Argentina
Allergol Immunopathol (Madr) 2000 Sep-Oct;28(5):267-71 Abstract quote
Since the detection of the first patient with hereditary angioedema (HA) in 1978, 88 new patients belonging to 16 families have been referred to our clinic. Eighty patients had Type I disease, 5 Type II, and 3 Type III (secondary).

We describe the clinical onset, frequent complications, diagnostic tests of the complement system, and abnormalities of the coagulation pathway linked to complement activation. Particular attention was paid to family members who could present succedaneum symptoms. The results of danazole and other therapies and protective and preventive treatment for surgery also are discussed.

Hereditary angioedema with a de novo mutation of exon 8 in the C1 inhibitor gene showing recurrent edema of the hands around the peripheral joints: importance for the differential diagnosis of joint swelling.

Sugiyama E, Ozawa T, Taki H, Maruyama M, Yamashita N, Ohta M, Hirata M, Kobayashi M.

First Department of Internal Medicine, Toyama Medical and Pharmaceutical University, Japan.

Arthritis Rheum 2001 Apr;44(4):974-7 Abstract quote
We describe a patient with hereditary angioedema (HAE), showing recurrent edema around the peripheral joints. Her symptoms began at the age of 18 with hand swelling distal to the wrist joints. Until she was referred to our hospital 3 years after her initial symptoms, she was still undiagnosed, although she was suspected of having rheumatoid arthritis. Laboratory examination showed reduced levels of CH50 and C4 with normal C3 levels.

The C1 inhibitor (C1-INH) was decreased to 5 mg/ml, with remarkably reduced activity. Although these findings were compatible with a diagnosis of HAE, there were no episodes of skin edema in her family. To establish the diagnosis, we carried out DNA analysis of the C1-INH gene, which revealed a newly identified de novo mutation of G to A at nucleotide 16869 in exon 8.

As described in this patient, localized edema around the peripheral joints may be the only manifestation of HAE. HAE should therefore be taken into consideration for the differential diagnosis of joint swelling.

Hereditary angioedema: a broad review for clinicians.

Nzeako UC, Frigas E, Tremaine WJ.

Division of Gastroenterology, E19B, Mayo Clinic, 200 First St SW, Rochester, MN 55905, USA.
Arch Intern Med 2001 Nov 12;161(20):2417-29 Abstract quote
Hereditary angioedema (HAE) is an autosomal dominant disease that afflicts 1 in 10,000 to 1 in 150,000 persons; HAE has been reported in all races, and no sex predominance has been found. It manifests as recurrent attacks of intense, massive, localized edema without concomitant pruritus, often resulting from one of several known triggers. However, attacks can occur in the absence of any identifiable initiating event.

Historically, 2 types of HAE have been described. However, a variant, possibly X-linked, inherited angioedema has recently been described, and tentatively it has been named "type 3" HAE. Signs and symptoms are identical in all types of HAE. Skin and visceral organs may be involved by the typically massive local edema. The most commonly involved viscera are the respiratory and gastrointestinal systems. Involvement of the upper airways can result in severe life-threatening symptoms, including the risk of asphyxiation, unless appropriate interventions are taken. Quantitative and functional analyses of C1 esterase inhibitor and complement components C4 and C1q should be performed when HAE is suspected. Acute exacerbations of the disease should be treated with intravenous purified C1 esterase inhibitor concentrate, where available.

Intravenous administration of fresh frozen plasma is also useful in acute HAE; however, it occasionally exacerbates symptoms. Corticosteroids, antihistamines, and epinephrine can be useful adjuncts but typically are not efficacious in aborting acute attacks. Prophylactic management involves long-term use of attenuated androgens or antifibrinolytic agents. Clinicians should keep this disorder in their differential diagnosis of unexplained, episodic cutaneous angioedema or abdominal pain.

HISTOLOGICAL TYPES CHARACTERIZATION

GENERAL

Histologic studies of chronic idiopathic urticaria.

Natbony SF, Phillips ME, Elias JM, Godfrey HP, Kaplan AP.
J Allergy Clin Immunol 1983 Feb;71(2):177-83 Abstract quote
Skin biopsy specimens were obtained from 43 consecutive patients with chronic idiopathic urticaria and from seven normal controls.

Of 43 patients, 42 had a non-necrotizing perivascular infiltrate composed primarily of mononuclear cells. There was no evidence of damage to vessel walls, of nuclear debris, or of extravasation of red blood cells, and most cells were seen around vessels rather than within the vessel wall. One patient had vasculitis with a neutrophilic infiltrate, nuclear debris, and positive immunofluorescence.

Quantitative cell counts revealed four times the number of mononuclear cells and 10 times the number of mast cells in urticaria biopsy sites vs normal skin. Thus chronic urticaria is characterized by an accumulation of mononuclear cells and mast cells with mast cell degranulation presumably associated with hive formation.

In our series, the characteristic lesion is not vasculitic. The stimulus responsible for the infiltration of skin with these cells is unknown.

Cutaneous inflammatory cell infiltrate in chronic idiopathic urticaria: comparison of patients with and without anti-FcepsilonRI or anti-IgE autoantibodies.

Sabroe RA, Poon E, Orchard GE, Lane D, Francis DM, Barr RM, Black MM, Black AK, Greaves MW.

Professorial Unit, St John's Institute of Dermatology, Guy's, King's College and St Thomas's Hospitals' Medical and Dental Schools, St Thomas's Hospital, London, United Kingdom.
J Allergy Clin Immunol 1999 Mar;103(3 Pt 1):484-93 Abstract quote
BACKGROUND: Previous studies defining the histopathologic features of patients with chronic idiopathic urticaria (CIU) were performed on wheals of uncertain duration and before the identification of functional autoantibodies against FcepsilonRI and/or IgE, now known to be present in approximately 30% of patients with CIU.

OBJECTIVE: We sought to determine the timing of the inflammatory infiltrate in the wheals of patients with CIU and to detect differences between patients with and without autoantibodies.

METHODS: Immunohistochemistry was used to identify neutrophils (neutrophil elastase), T lymphocytes (CD3), and activated eosinophils (EG2) in biopsy specimens from uninvolved skin and wheals present for less than 4 hours and greater than 12 hours in 22 patients with CIU, as well as in biopsy specimens from the skin of 12 healthy control subjects. Patients were identified as having functional autoantibodies on the basis of their serum-evoked histamine release in vitro from the basophils of 2 healthy donors.

RESULTS: EG2(+), neutrophil elastase+, and, to a lesser extent, CD3(+) cells were found in greater numbers in wheals undergoing biopsy at less than 4 and greater than 12 hours than in uninvolved skin (P <.05). Patients without autoantibodies (n = 12) had significantly more EG2(+) cells in wheals of greater than 12 hours' duration than patients with autoantibodies (n = 10; P =.02). There was no other difference between patients with and without autoantibodies in the cutaneous cellular infiltrate.

CONCLUSION: Neutrophil and eosinophil accumulation occurs early in the evolution of a wheal in patients with CIU, but eosinophil activation may occur later or be more persistent in patients without autoantibodies.

VARIANTS

CHOLINERGIC

Cholinergic Urticaria, a New Pathogenic Concept: Hypohidrosis due to Interference with the Delivery of Sweat to the Skin Surface.

Kobayashi H, Aiba S, Yamagishi T, Tanita M, Hara M, Saito H, Tagami H.

Department of Dermatology, Tohoku University School of Medicine, Sendai, Japan.

Dermatology 2002;204(3):173-8 Abstract quote
Background: Acetylcholine has been suspected to be a pathogenetic factor for cholinergic urticaria (CU), without definite evidence. In contrast, there are scattered reports of CU associated with acquired generalized hypohidrosis. We have recently examined 2 patients with CU in both of whom we noticed the presence of extensive hypohidrosis that occurred only in winter.

Objective: In these 2 patients, acquired hypohidrosis due to superficial obstruction of the acrosyringium was suspected as the cause. Both case 1, a 22-year-old Japanese man, and case 2, a 21-year-old Japanese man, began to have anhidrosis and numerous red macules on their body whenever they felt hot in winter. These symptoms ceased to appear in summer.

Methods: We studied histologically their lesional skin in addition to provocation tests for CU.

Results: The diagnosis of CU was confirmed by the provocation of typical wheals after physical exercise in both cases. Histological study revealed findings suggestive of the presence of occlusion of the superficial acrosyringium.

Conclusion: We think that such a hypohidrosis due to occlusion of superficial sweat ducts may also play a role in many other patients with CU of unknown etiology that becomes exacerbated in winter when sweating is not a frequent event.

NEUTROPHILIC URTICARIA

Neutrophilic urticaria: clinical features, histological changes and possible mechanisms.

Toppe E, Haas N, Henz BM.

Department of Dermatology, Virchow Klinikum, Humboldt Universitat, Berlin, Germany.
Br J Dermatol 1998 Feb;138(2):248-53 Abstract quote
Neutrophilic urticaria (NU) is a histologically defined entity, but its clinical and pathogenetic aspects are poorly understood.

We investigated 22 NU patients whom we identified by examining 118 biopsies of weals. The patients comprised 11 of 20 with acute urticaria, nine of 49 with chronic urticaria, one of 10 with cold urticaria and one of 10 controls undergoing prick tests.

Clinically, NU patients had a shorter mean duration of disease than other urticaria patients and significantly increased erythrocyte sedimentation rate and leucocytosis. Histologically, not only neutrophil counts, but to a lesser extent also eosinophil counts and mononuclear cell infiltrates were significantly increased in lesional skin of NU, and there was more marked vasodilatation and endothelial swelling. On immunohistochemistry, increased tumour necrosis factor alpha and interleukin (IL)-3 expression was noted, compared with other urticarias, whereas IL-8 expression was only minor.

These data characterize NU as an acute phase urticarial reaction associated with an intense inflammatory infiltrate and marked upregulation of some mast cell-derived cytokines.

PROGNOSIS AND TREATMENT CHARACTERIZATION

PROGNOSTIC FACTORS

AUTOANTIBODIES

Chronic idiopathic urticaria: comparison of the clinical features of patients with and without anti-FcepsilonRI or anti-IgE autoantibodies.

Sabroe RA, Seed PT, Francis DM, Barr RM, Black AK, Greaves MW.

Professorial Unit, St John's Institute of Dermatology, Guy's, King's College and St Thomas's Hospitals' Medical and Dental Schools, London, United Kingdom.
J Am Acad Dermatol 1999 Mar;40(3):443-50 Abstract quote
BACKGROUND: Previous studies defining the clinical features of patients with chronic idiopathic urticaria (CIU) were performed before the identification of functional autoantibodies against FcepsilonRI and/or IgE, now known to be present in approximately 30% of patients with CIU.

OBJECTIVE: Our purpose was to determine whether there are differences between patients with and those without autoantibodies in the clinical features or severity of CIU.

METHODS: The clinical features of 107 patients with CIU were evaluated prospectively. Patients were identified as having functional autoantibodies on the basis of the serum-evoked histamine release in vitro from the basophils of 2 healthy donors.

RESULTS: Patients with autoantibodies (31%) had more wheals (P = .005), a wider distribution of wheals (P = .009), higher itch scores for the most severe episodes of itching (P = .002), more systemic symptoms (P = .03), and lower serum IgE levels (P < .0005) than patients without autoantibodies.

CONCLUSION: The presence of autoantibodies indicates a subset of patients with more severe CIU.

TREATMENT

CYCLOSPORINE

Randomized double-blind study of cyclosporin in chronic 'idiopathic' urticaria.

Grattan CE, O'Donnell BF, Francis DM, Niimi N, Barlow RJ, Seed PT, Kobza Black A, Greaves MW.

Dermatology Centre, West Norwich Hospital, Norwich NR2 3TU, UK.
Br J Dermatol 2000 Aug;143(2):365-72 Abstract quote
BACKGROUND: Histamine-releasing activity (HRA) is detectable in up to 50% of patients with chronic ordinary urticaria.

OBJECTIVES: To determine the effect of cyclosporin on clinical features and HRA in patients with chronic urticaria.

METHODS: Thirty patients with severe unremitting disease, responding poorly to antihistamines and showing a positive autologous serum skin test (ASST) as a marker of HRA, were randomized to 4 mg kg-1 daily of cyclosporin (Sandimmun, n = 20) or placebo (n = 10) for 4 weeks. Non-responders were offered open-label cyclosporin for 4 weeks. All were followed for up to 20 weeks or until clinical relapse; all took cetirizine 20 mg daily throughout the study. The primary measure of efficacy was a daily urticaria activity score (UAS) of weal numbers and itch (maximum score 42 per week). A positive response was defined as a reduction to < 25% of baseline weekly UAS and relapse as a return to > 75%. The effect of cyclosporin on serum HRA was assessed by in vitro basophil histamine release assays and ASSTs before and after treatment.

RESULTS: Twenty-nine patients (19 active, 10 controls) completed the randomized trial medication. Eight of 19 on active treatment but none on placebo had responded at 4 weeks (P < 0.05). Three others on active drug met the criterion for response at 2 weeks but not at 4 weeks. Mean reduction in UAS between weeks 0 and 4 was 12.7 (95% confidence interval, CI 6.6-18.8) for active and 2.3 (95% CI - 3.3-7.9) for placebo (P = 0.005). Seventeen non-responders (seven randomized to active and 10 to placebo) chose open-label cyclosporin and 11 responded after 4 weeks. Six of the eight randomized active drug responders relapsed within 6 weeks. Of the 19 responders to randomized and open-label cyclosporin, five (26%) had not relapsed by the study end-point. Mean in vitro serum HRA fell from 36% (95% CI 22-49%) to 5% (95% CI 1-8%) after cyclosporin treatment (n = 11, P < 0.0001). The ASST response to post-treatment serum was also reduced (P < 0.05).

CONCLUSIONS: This study shows that cyclosporin is effective for chronic urticaria and provides further evidence for a role of histamine-releasing autoantibodies in the pathogenesis of this chronic 'idiopathic' disease.

IMMUNOGLOBULIN, INTRAVENOUS

Intravenous immunoglobulin in autoimmune chronic urticaria.

O'Donnell BF, Barr RM, Black AK, Francis DM, Kermani F, Niimi N, Barlow RJ, Winkelmann RK, Greaves MW.

St John's Institute of Dermatology, United Medical and Dental School, St Thomas' Hospital, London.
Br J Dermatol 1998 Jan;138(1):101-6 Abstract quote
Histamine releasing autoantibodies play a central role in the pathogenesis of chronic urticaria (CU) in approximately 30% of affected patients.

We investigated the therapeutic effect of high-dose intravenous immunoglobulin (IVIG) on disease activity in patients with severe CU of autoimmune aetiology. Autoimmune urticaria was diagnosed by the development of a weal-and-flare reaction to the intradermal injection of autologous serum and by serum-induced histamine release from the basophil leucocytes of healthy donors in vitro. Ten patients with severe, autoimmune CU, poorly responsive to conventional treatment, were treated with IVIG 0.4 g/kg per day for 5 days. The outcome on cutaneous wealing and itch was monitored using urticaria activity scores, visual analogue scales and autologous intradermal serum tests. Clinical benefit was noted in nine of 10 patients: three patients continue in prolonged complete remissions (3 years follow-up), two had temporary complete remissions, and symptoms in four patients improved subsequent to treatment.

There was significant improvement in the urticaria activity scores and visual analogue scores at 2 (P < 0.01) and 6 weeks (P < 0.01) post-IVIG compared with the baseline values (Wilcoxon matched pairs). The diminution in urticarial activity in the majority of patients corresponded with a reduced weal-and-flare response to the intradermal injection of autologous post-treatment serum compared with the pretreatment serum. Minor side-effects were common, but there were no serious or long-term adverse effects. IVIG represents a novel therapeutic option in selected patients with recalcitrant CU associated with histamine releasing autoantibodies.

Henry JB. Clinical Diagnosis and Management by Laboratory Methods. Twentieth Edition. WB Saunders. 2001.
Weedon D. Weedon's Skin Pathology. Churchill Livingstone. 1997.
Fitzpatrick's Dermatology in General Medicine. 5th Edition. McGraw-Hill. 1999.

Commonly Used Terms

Pruritis

Skin Rash

Internet Links

Last Updated 10/28/2002

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Copyright � 2002 The Doctor's Doctor

DISEASE ASSOCIATIONS	CHARACTERIZATION
DRUGS
Drug-induced urticaria and angioedema: pathomechanisms and frequencies in a developing country and in developed countries. Greaves MW, Hussein SH. Department of Dermatology, Hospital Kuala Lumpur, Malaysia.	Int Arch Allergy Immunol 2002 May;128(1):1-7 Abstract quote A careful drug history should be obtained from all patients with acute or chronic urticaria/angioedema, especially in the elderly. Although strictly comparable data are lacking, drug-induced urticaria appears to be more common in developed countries than in Malaysia, at least in a Hospital setting. Culprit drugs include antibiotics, analgesics and contrast media. Pseudoallergic drug-induced urticaria mimicks true allergic urticaria, but without an evident immunological basis, and is at least as common as the allergic type. In Malaysia, and in many other countries compulsory, ingredient labelling of 'traditional' medicines would do much to reduce the frequency of drug-induced urticaria.
LACTOSE INTOLERANCE
Familial aquagenic urticaria associated with familial lactose intolerance. Treudler R, Tebbe B, Steinhoff M, Orfanos CE. Department of Dermatology, University Medical Centre Benjamin Franklin, The Free University of Berlin, Germany.	J Am Acad Dermatol 2002 Oct;47(4):611-3 Abstract quote Aquagenic urticaria is a rare disorder characterized by the occurrence of pruritus and wheals after temporary contact with water. The familial occurrence of aquagenic urticaria over 3 generations is reported here in association with familial lactose intolerance, a condition in which the enzyme lactase encoded on chromosome 2, is deficient. In two patients, a young man and his mother, we verified the appearance of pruritic hives 5 to 10 minutes after contact with water of any temperature. Other types of physical urticaria were absent, and mastocytosis was excluded by extensive laboratory investigations; lactose intolerance was confirmed in both patients by H(2)-exhalation test. In these patients the clinical symptoms did not respond to antihistamines or UV-radiation therapy. Four other members of the family had wheals from water contact, two of whom had lactose intolerance. Two other members had lactose intolerance only. Although the association of aquagenic urticaria with lactose intolerance may be coincidental, attention is drawn to the fact that the 2 conditions, known to be familial, may coexist in the same family, possibly based on an association of gene loci.
MYCOSIS FUNGOIDES
Cold urticaria in a patient with mycosis fungoides. Koay J, Jones D, Duvic M. Baylor College of Medicine, Houston, Texas 77030, USA.	J Am Acad Dermatol 2002 Oct;47(4):608-10 Abstract quote We report what we believe to be the first documentation of a patient with both cold urticaria and mycosis fungoides. The patient described a marked worsening of his long-standing lesions of mycosis fungoides at the same time as the onset of cold sensitivity. We believe this suggests a possible association between these 2 rare diseases.

PATHOGENESIS	CHARACTERIZATION
GENERAL
The pathogenesis of chronic idiopathic urticaria. Sabroe RA, Greaves MW. St John's Institute of Dermatology, St Thomas' Hospital, London, England.	Arch Dermatol 1997 Aug;133(8):1003-8 Abstract quote Chronic idiopathic urticaria (CIU) can be extremely disabling and difficult to treat, with little response to antihistamine therapy. The pathogenic mechanisms of the disease are not well understood, but the primary effector cell is the mast cell. Release of mast cell mediators can cause inflammation and accumulation and activation of other cells, including eosinophils, neutrophils, and possibly basophils. Recent work has demonstrated that about one third of patients with CIU have circulating functional histamine-releasing autoantibodies that bind to the high-affinity IgE receptor (Fc epsilon RI) or, less commonly, to IgE; mast cell-specific histamine-releasing activity that has not yet been fully characterized; no identifiable circulating histamine-releasing activity. The mainstay of treatment of CIU consists of antithistamines, but immunotherapy using plasmapheresis, intravenous immunoglobulin, and cyclosporin may be valuable in severely affected patients with treatment-resistant disease. The response to immunomodulation and the recent finding of an association with HLA DR4 lend further support for an autoimmune basis to CIU in some patients.
AUTOANTIBODIES
Autoantibodies against the high-affinity IgE receptor as a cause of histamine release in chronic urticaria. Hide M, Francis DM, Grattan CE, Hakimi J, Kochan JP, Greaves MW. St. John's Institute of Dermatology, United Medical School, Guy's Hospital, London, United Kingdom.	N Engl J Med 1993 Jun 3;328(22):1599-604 Abstract quote BACKGROUND. Most urticarias are induced by vasoactive mediators such as histamine released from mast cells. Although mast cells are activated by allergens through cross-linking of cell-surface--bound IgE, this mechanism does not appear to explain most cases of chronic urticaria, which, when allergic, infectious, drug-induced, or physical causes cannot be identified, are classified as idiopathic. METHODS. We recruited 26 patients with chronic idiopathic urticaria, in whom intradermal injection of autologous serum caused a wheal-and-flare response. Serum from four patients that induced marked histamine release from basophils from a donor with very low serum IgE levels was studied with respect to the IgE dependence of the histamine release, the activity of the IgG fractions, and the neutralizing effect of a recombinant preparation of the soluble extracellular domain of the alpha subunit of the high-affinity IgE receptor (sFc epsilon RI alpha). RESULTS. The histamine-releasing activity of the serum was abolished by passive sensitization of basophils with myeloma IgE, enhanced after dissociation of IgE by treatment with lactic acid, and induced by IgG fractions from the serum of all four patients. Preincubation of the serum and isolated IgG with sFc epsilon RI alpha resulted in almost complete neutralization. CONCLUSIONS. Histamine-releasing IgG autoantibodies against the alpha subunit of the high-affinity IgE receptor are present in the circulation of some patients with chronic urticaria. Autoantibody-induced cross-linking of IgE receptors may be an important mechanism in the pathogenesis of chronic urticaria and other diseases mediated by mast cells.
CHROMOSOMAL ABNORMALITIES
New Mutations of CIAS1 That Are Responsible for Muckle-Wells Syndrome and Familial Cold Urticaria: A Novel Mutation Underlies Both Syndromes. Dode C, Le Du N, Cuisset L, Letourneur F, Berthelot JM, Vaudour G, Meyrier A, Watts RA, Scott DG, Nicholls A, Granel B, Frances C, Garcier F, Edery P, Boulinguez S, Domergues JP, Delpech M, Grateau G. INSERM EMI 00-05, Institut Cochin, Hopital Cochin, Universite Paris V, Paris, France.	Am J Hum Genet 2002 Jun;70(6):1498-506 Abstract quote Mutations of CIAS1 have recently been shown to underlie familial cold urticaria (FCU) and Muckle-Wells syndrome (MWS), in three families and one family, respectively. These rare autosomal dominant diseases are both characterized by recurrent inflammatory crises that start in childhood and that are generally associated with fever, arthralgia, and urticaria. The presence of sensorineural deafness that occurs later in life is characteristic of MWS. Amyloidosis of the amyloidosis-associated type is the main complication of MWS and is sometimes associated with FCU. In FCU, cold exposure is the triggering factor of the inflammatory crisis. We identified CIAS1 mutations, all located in exon 3, in nine unrelated families with MWS and in three unrelated families with FCU, originating from France, England, and Algeria. Five mutations-namely, R260W, D303N, T348M, A439T, and G569R-were novel. The R260W mutation was identified in two families with MWS and in two families with FCU, of different ethnic origins, thereby demonstrating that a single CIAS1 mutation may cause both syndromes. This result indicates that modifier genes are involved in determining either a MWS or a FCU phenotype. The finding of the G569R mutation in an asymptomatic individual further emphasizes the importance of such modifier a gene (or genes) in determining the disease phenotype. Identification of this gene (or these genes) is likely to have significant therapeutic implications for these severe diseases.
CYTOKINES
Upregulation of TNF-alpha and IL-3 expression in lesional and uninvolved skin in different types of urticaria. Hermes B, Prochazka AK, Haas N, Jurgovsky K, Sticherling M, Henz BM. Neukolln Hospital, Berlin, Germany.	J Allergy Clin Immunol 1999 Feb;103(2 Pt 1):307-14 Abstract quote BACKGROUND: Although mast cells are known to secrete a broad spectrum of proinflammatory and immunomodulatory cytokines, the role of these molecules in mast cell-dependent cutaneous inflammation is not clear. OBJECTIVE: We decided to study biopsy specimens from lesional and nonlesional skin of patients with acute, chronic recurrent, delayed pressure, and cold urticaria; from fleeting wheals of prick test reactions to allergens; and from normal skin of nonallergic subjects. METHODS: Cryostat sections were stained by immunohistochemistry with antibodies against IL-3, IL-8, TNF-alpha, and mast cell-specific tryptase. In serial sections with tryptase and each cytokine, reactivity of mast cells was studied as well. RESULTS: Compared with normal skin and prick test reactions, immunoreactivity for TNF-alpha and IL-3 was significantly increased on endothelial and perivascular cells of the upper dermis in all urticaria lesions. In nonlesional skin comparable upregulation was noted on endothelial cells and for TNF-alpha on perivascular cells of patients with delayed pressure urticaria. In addition, TNF-alpha was expressed throughout the epidermis in lesional and nonlesional skin of patients with all types of urticaria, but not in normal control subjects. Sequential biopsy specimens from patients with cold urticaria showed upregulation of TNF-alpha and IL-3 on endothelial cells 30 minutes after elicitation of lesions with an ice cube. In contrast to these findings, epidermal immunoreactivity, as well as endothelial and perivascular cell expression of IL-8, were only slightly altered in urticaria compared with normal skin. In sequentially stained sections, few tryptase-positive mast cells reacted to TNF-alpha, few reacted to IL-3 in pressure urticaria only, and practically none stained for IL-8. CONCLUSION: These findings suggest that the cytokines studied here are involved in the pathology of urticaria, possibly by inducing subthreshold inflammation in endothelial cells of uninvolved skin.
Immune profiles of patients with chronic idiopathic urticaria. Piconi S, Trabattoni D, Iemoli E, Fusi ML, Villa ML, Milazzo F, Clerici M. First Department of Infectious Disease and Allergy Unit, L. Sacco Hospital, Milan, Italy	Int Arch Allergy Immunol 2002 May;128(1):59-66 Abstract quote Background: The immunologic characterization of chronic idiopathic urticaria (CIU) is still incomplete. In particular, it is not known if positivity to the intradermal autologous serum skin test (ASST) identifies an immunologic subset of CIU patients. Methods: Nineteen CIU patients and 15 healthy controls were enrolled in the study. A diagnostic flowchart was designed to select CIU patients, who were then analyzed by ASST. Cytokine and chemokine production and the expression of adhesion molecules was measured in patients and controls. Results: In CIU patients compared to controls, it was found that (1) TNF-alpha, IL-10, MIP-1alpha and RANTES production was augmented and IL-2 and INF-gamma reduced, and (2) CD44, CD11a and CD62L expression on CD4 and CD8 cells was augmented. Additionally, TNF-alpha and chemokine production was significantly increased in CIU patients with a negative ASST (p-; n = 10) compared to patients with a positive response to the test. Conclusions: The presence of an inflammatory process in CIU patients is suggested by the findings that the production of both TNF-alpha and chemokines as well as the expression of adhesion molecules is increased in these patients. Similarly to what is seen in rheumatoid arthritis, augmented IL-10 production might be secondary to the attempt to hamper the inflammatory milieu. Immune profiles are particularly altered in CIU p- patients, in whom a more aggressive therapeutic strategy might be considered.
MAST CELLS
Mast cell number and phenotype in chronic idiopathic urticaria. Smith CH, Kepley C, Schwartz LB, Lee TH. Department of Allergy & Respiratory Medicine, United Medical School, Guy's Hospital, London, England.	J Allergy Clin Immunol 1995 Sep;96(3):360-4 Abstract quote BACKGROUND: Increased levels of histamine have been previously demonstrated in patients with chronic idiopathic urticaria. OBJECTIVE: The purpose of the study was to determine whether increased numbers of mast cells are present in lesional skin from such patients. METHODS: Mast cells have been quantified in lesional (n = 11) and nonlesional (n = 9) skin from patients with chronic idiopathic urticaria and compared with site-matched skin from healthy control subjects (n = 10). Mast cells were identified by using a sensitive, double-labeling immunohistochemical technique with specific monoclonal antibodies to mast cell tryptase and chymase and quantified under light microscopy. RESULTS: No significant differences in mast cell numbers from lesional, nonlesional, or control skin were observed (p > 0.1, Student's t test). In both patients with urticaria and control subjects, more than 99% of cutaneous mast cells contained tryptase and chymase. CONCLUSIONS: These data indicate that increased skin histamine in chronic idiopathic urticaria is not caused by increased mast cells and may alternatively reflect an increase in histamine content per mast cell, enhanced mast cell activation, or recruitment of basophils into skin in patients with chronic idiopathic urticaria

HISTOLOGICAL TYPES	CHARACTERIZATION
GENERAL
Histologic studies of chronic idiopathic urticaria. Natbony SF, Phillips ME, Elias JM, Godfrey HP, Kaplan AP.	J Allergy Clin Immunol 1983 Feb;71(2):177-83 Abstract quote Skin biopsy specimens were obtained from 43 consecutive patients with chronic idiopathic urticaria and from seven normal controls. Of 43 patients, 42 had a non-necrotizing perivascular infiltrate composed primarily of mononuclear cells. There was no evidence of damage to vessel walls, of nuclear debris, or of extravasation of red blood cells, and most cells were seen around vessels rather than within the vessel wall. One patient had vasculitis with a neutrophilic infiltrate, nuclear debris, and positive immunofluorescence. Quantitative cell counts revealed four times the number of mononuclear cells and 10 times the number of mast cells in urticaria biopsy sites vs normal skin. Thus chronic urticaria is characterized by an accumulation of mononuclear cells and mast cells with mast cell degranulation presumably associated with hive formation. In our series, the characteristic lesion is not vasculitic. The stimulus responsible for the infiltration of skin with these cells is unknown.
Cutaneous inflammatory cell infiltrate in chronic idiopathic urticaria: comparison of patients with and without anti-FcepsilonRI or anti-IgE autoantibodies. Sabroe RA, Poon E, Orchard GE, Lane D, Francis DM, Barr RM, Black MM, Black AK, Greaves MW. Professorial Unit, St John's Institute of Dermatology, Guy's, King's College and St Thomas's Hospitals' Medical and Dental Schools, St Thomas's Hospital, London, United Kingdom.	J Allergy Clin Immunol 1999 Mar;103(3 Pt 1):484-93 Abstract quote BACKGROUND: Previous studies defining the histopathologic features of patients with chronic idiopathic urticaria (CIU) were performed on wheals of uncertain duration and before the identification of functional autoantibodies against FcepsilonRI and/or IgE, now known to be present in approximately 30% of patients with CIU. OBJECTIVE: We sought to determine the timing of the inflammatory infiltrate in the wheals of patients with CIU and to detect differences between patients with and without autoantibodies. METHODS: Immunohistochemistry was used to identify neutrophils (neutrophil elastase), T lymphocytes (CD3), and activated eosinophils (EG2) in biopsy specimens from uninvolved skin and wheals present for less than 4 hours and greater than 12 hours in 22 patients with CIU, as well as in biopsy specimens from the skin of 12 healthy control subjects. Patients were identified as having functional autoantibodies on the basis of their serum-evoked histamine release in vitro from the basophils of 2 healthy donors. RESULTS: EG2(+), neutrophil elastase+, and, to a lesser extent, CD3(+) cells were found in greater numbers in wheals undergoing biopsy at less than 4 and greater than 12 hours than in uninvolved skin (P <.05). Patients without autoantibodies (n = 12) had significantly more EG2(+) cells in wheals of greater than 12 hours' duration than patients with autoantibodies (n = 10; P =.02). There was no other difference between patients with and without autoantibodies in the cutaneous cellular infiltrate. CONCLUSION: Neutrophil and eosinophil accumulation occurs early in the evolution of a wheal in patients with CIU, but eosinophil activation may occur later or be more persistent in patients without autoantibodies.
VARIANTS
CHOLINERGIC
Cholinergic Urticaria, a New Pathogenic Concept: Hypohidrosis due to Interference with the Delivery of Sweat to the Skin Surface. Kobayashi H, Aiba S, Yamagishi T, Tanita M, Hara M, Saito H, Tagami H. Department of Dermatology, Tohoku University School of Medicine, Sendai, Japan.	Dermatology 2002;204(3):173-8 Abstract quote Background: Acetylcholine has been suspected to be a pathogenetic factor for cholinergic urticaria (CU), without definite evidence. In contrast, there are scattered reports of CU associated with acquired generalized hypohidrosis. We have recently examined 2 patients with CU in both of whom we noticed the presence of extensive hypohidrosis that occurred only in winter. Objective: In these 2 patients, acquired hypohidrosis due to superficial obstruction of the acrosyringium was suspected as the cause. Both case 1, a 22-year-old Japanese man, and case 2, a 21-year-old Japanese man, began to have anhidrosis and numerous red macules on their body whenever they felt hot in winter. These symptoms ceased to appear in summer. Methods: We studied histologically their lesional skin in addition to provocation tests for CU. Results: The diagnosis of CU was confirmed by the provocation of typical wheals after physical exercise in both cases. Histological study revealed findings suggestive of the presence of occlusion of the superficial acrosyringium. Conclusion: We think that such a hypohidrosis due to occlusion of superficial sweat ducts may also play a role in many other patients with CU of unknown etiology that becomes exacerbated in winter when sweating is not a frequent event.
NEUTROPHILIC URTICARIA
Neutrophilic urticaria: clinical features, histological changes and possible mechanisms. Toppe E, Haas N, Henz BM. Department of Dermatology, Virchow Klinikum, Humboldt Universitat, Berlin, Germany.	Br J Dermatol 1998 Feb;138(2):248-53 Abstract quote Neutrophilic urticaria (NU) is a histologically defined entity, but its clinical and pathogenetic aspects are poorly understood. We investigated 22 NU patients whom we identified by examining 118 biopsies of weals. The patients comprised 11 of 20 with acute urticaria, nine of 49 with chronic urticaria, one of 10 with cold urticaria and one of 10 controls undergoing prick tests. Clinically, NU patients had a shorter mean duration of disease than other urticaria patients and significantly increased erythrocyte sedimentation rate and leucocytosis. Histologically, not only neutrophil counts, but to a lesser extent also eosinophil counts and mononuclear cell infiltrates were significantly increased in lesional skin of NU, and there was more marked vasodilatation and endothelial swelling. On immunohistochemistry, increased tumour necrosis factor alpha and interleukin (IL)-3 expression was noted, compared with other urticarias, whereas IL-8 expression was only minor. These data characterize NU as an acute phase urticarial reaction associated with an intense inflammatory infiltrate and marked upregulation of some mast cell-derived cytokines.

Ordinary urticaria	Recurrent or episodic urticaria not in the categories below
Physical urticaria (defined by the triggering stimulus)	Adrenergic urticaria Aquagenic urticaria Cholinergic urticaria Cold urticaria Delayed pressure urticaria Dermographism Exercise-induced anaphylaxis Localized heat urticaria Solar urticaria Vibratory angioedema
Contact urticaria	Induced by biologic or chemical skin contact
Urticarial vasculitis	Defined by vasculitis as shown by skin biopsy specimen
Angioedema	Without wheals

Disease Associations
Pathogenesis
Laboratory/Radiologic/Other Diagnostic Testing
Gross Appearance and Clinical Variants
Histopathological Features and Variants
Prognosis and Treatment
Commonly Used Terms
Internet Links

LABORATORY/RADIOLOGIC/ OTHER TESTS	CHARACTERIZATION
RADIOLOGIC
LABORATORY MARKERS
Preliminary identification of a low molecular weight serological mediator in chronic idiopathic urticaria. Grattan CE, Hamon CG, Cowan MA, Leeming RJ. Department of Dermatology, General Hospital, Birmingham, U.K.	Br J Dermatol 1988 Aug;119(2):179-83 Abstract quote Sixteen patients with chronic idiopathic urticaria were skin tested with their own serum, IO with autologous plasma and five with serum that had been heated to 56 degrees C to inactivate complement. Eight showed a weal and flare response to whole serum, four to plasma and five to heat-treated serum. All serum-positive patients showed the same response to their own plasma and to heated serum, indicating that the mediator concerned is not generated by clotting and is not dependent on a functioning complement pathway. Three control subjects were negative to autologous serum, plasma and heated serum. Local tachyphylaxis was demonstrated in five serum-positive patients on reinjection of the same site with autologous serum on 3 consecutive days. This raises the possibility that the serological mediator may be acting by mast cell degranulation or directly on receptors in blood vessels and that repeated injections could induce a change in the number of receptors. Passage of whole autologous serum from four serum-positive patients through ultrafiltration membranes showed that fractions with a molecular weight of less than 30,000 daltons were still able to produce a positive skin test response, but those less than 1000 daltons were not. All serum fractions from two serum-negative patients and three normal controls were negative. Whole autologous serum from five serum-positive patients and two control subjects were separated by column chromatography. On skin testing with pooled fractions, the greatest response was produced by fractions of 10,000-15,000 daltons in the serum-positive patients, but there was no response in the controls.

PROGNOSIS AND TREATMENT	CHARACTERIZATION
PROGNOSTIC FACTORS
AUTOANTIBODIES
Chronic idiopathic urticaria: comparison of the clinical features of patients with and without anti-FcepsilonRI or anti-IgE autoantibodies. Sabroe RA, Seed PT, Francis DM, Barr RM, Black AK, Greaves MW. Professorial Unit, St John's Institute of Dermatology, Guy's, King's College and St Thomas's Hospitals' Medical and Dental Schools, London, United Kingdom.	J Am Acad Dermatol 1999 Mar;40(3):443-50 Abstract quote BACKGROUND: Previous studies defining the clinical features of patients with chronic idiopathic urticaria (CIU) were performed before the identification of functional autoantibodies against FcepsilonRI and/or IgE, now known to be present in approximately 30% of patients with CIU. OBJECTIVE: Our purpose was to determine whether there are differences between patients with and those without autoantibodies in the clinical features or severity of CIU. METHODS: The clinical features of 107 patients with CIU were evaluated prospectively. Patients were identified as having functional autoantibodies on the basis of the serum-evoked histamine release in vitro from the basophils of 2 healthy donors. RESULTS: Patients with autoantibodies (31%) had more wheals (P = .005), a wider distribution of wheals (P = .009), higher itch scores for the most severe episodes of itching (P = .002), more systemic symptoms (P = .03), and lower serum IgE levels (P < .0005) than patients without autoantibodies. CONCLUSION: The presence of autoantibodies indicates a subset of patients with more severe CIU.
TREATMENT
CYCLOSPORINE
Randomized double-blind study of cyclosporin in chronic 'idiopathic' urticaria. Grattan CE, O'Donnell BF, Francis DM, Niimi N, Barlow RJ, Seed PT, Kobza Black A, Greaves MW. Dermatology Centre, West Norwich Hospital, Norwich NR2 3TU, UK.	Br J Dermatol 2000 Aug;143(2):365-72 Abstract quote BACKGROUND: Histamine-releasing activity (HRA) is detectable in up to 50% of patients with chronic ordinary urticaria. OBJECTIVES: To determine the effect of cyclosporin on clinical features and HRA in patients with chronic urticaria. METHODS: Thirty patients with severe unremitting disease, responding poorly to antihistamines and showing a positive autologous serum skin test (ASST) as a marker of HRA, were randomized to 4 mg kg-1 daily of cyclosporin (Sandimmun, n = 20) or placebo (n = 10) for 4 weeks. Non-responders were offered open-label cyclosporin for 4 weeks. All were followed for up to 20 weeks or until clinical relapse; all took cetirizine 20 mg daily throughout the study. The primary measure of efficacy was a daily urticaria activity score (UAS) of weal numbers and itch (maximum score 42 per week). A positive response was defined as a reduction to < 25% of baseline weekly UAS and relapse as a return to > 75%. The effect of cyclosporin on serum HRA was assessed by in vitro basophil histamine release assays and ASSTs before and after treatment. RESULTS: Twenty-nine patients (19 active, 10 controls) completed the randomized trial medication. Eight of 19 on active treatment but none on placebo had responded at 4 weeks (P < 0.05). Three others on active drug met the criterion for response at 2 weeks but not at 4 weeks. Mean reduction in UAS between weeks 0 and 4 was 12.7 (95% confidence interval, CI 6.6-18.8) for active and 2.3 (95% CI - 3.3-7.9) for placebo (P = 0.005). Seventeen non-responders (seven randomized to active and 10 to placebo) chose open-label cyclosporin and 11 responded after 4 weeks. Six of the eight randomized active drug responders relapsed within 6 weeks. Of the 19 responders to randomized and open-label cyclosporin, five (26%) had not relapsed by the study end-point. Mean in vitro serum HRA fell from 36% (95% CI 22-49%) to 5% (95% CI 1-8%) after cyclosporin treatment (n = 11, P < 0.0001). The ASST response to post-treatment serum was also reduced (P < 0.05). CONCLUSIONS: This study shows that cyclosporin is effective for chronic urticaria and provides further evidence for a role of histamine-releasing autoantibodies in the pathogenesis of this chronic 'idiopathic' disease.
IMMUNOGLOBULIN, INTRAVENOUS
Intravenous immunoglobulin in autoimmune chronic urticaria. O'Donnell BF, Barr RM, Black AK, Francis DM, Kermani F, Niimi N, Barlow RJ, Winkelmann RK, Greaves MW. St John's Institute of Dermatology, United Medical and Dental School, St Thomas' Hospital, London.	Br J Dermatol 1998 Jan;138(1):101-6 Abstract quote Histamine releasing autoantibodies play a central role in the pathogenesis of chronic urticaria (CU) in approximately 30% of affected patients. We investigated the therapeutic effect of high-dose intravenous immunoglobulin (IVIG) on disease activity in patients with severe CU of autoimmune aetiology. Autoimmune urticaria was diagnosed by the development of a weal-and-flare reaction to the intradermal injection of autologous serum and by serum-induced histamine release from the basophil leucocytes of healthy donors in vitro. Ten patients with severe, autoimmune CU, poorly responsive to conventional treatment, were treated with IVIG 0.4 g/kg per day for 5 days. The outcome on cutaneous wealing and itch was monitored using urticaria activity scores, visual analogue scales and autologous intradermal serum tests. Clinical benefit was noted in nine of 10 patients: three patients continue in prolonged complete remissions (3 years follow-up), two had temporary complete remissions, and symptoms in four patients improved subsequent to treatment. There was significant improvement in the urticaria activity scores and visual analogue scores at 2 (P < 0.01) and 6 weeks (P < 0.01) post-IVIG compared with the baseline values (Wilcoxon matched pairs). The diminution in urticarial activity in the majority of patients corresponded with a reduced weal-and-flare response to the intradermal injection of autologous post-treatment serum compared with the pretreatment serum. Minor side-effects were common, but there were no serious or long-term adverse effects. IVIG represents a novel therapeutic option in selected patients with recalcitrant CU associated with histamine releasing autoantibodies.