Hello all.
Sorry I haven't been posting lately. I have been putting in some long hours in at work and haven't had much time to do much by the time I get home.
Anyway I have gathered together some of my research information and going to copy it here for all to read.
I hope this will help give a little more detailed analysis of this condition called Urticaria. It also contains references as to who and where the research is being done. Keep in mind though, reading this will take some time, so bare with me. Thanks
Hogan Grimm

Preview: Urticaria is one of the most common dermatologic problems seen by primary care physicians and often a source of frustration for patient and physician alike. Pinpointing the cause may be challenging--or impossible--because of the many and varied triggers. Drs Krishnaswamy and Youngberg shed light on this common condition, describing the diagnostic considerations in evaluation of acute and chronic cases and discussing the variety of pharmacologic options available.
Krishnaswamy G, Youngberg G. Acute and chronic urticaria: challenges and considerations for primary care physicians. Postgrad Med 2001;109(2):107-23

Urticaria affects 15% to 25% of people at some point in their lifetime (1). In some cases, the disorder is relatively mild, recurrent, and frustrating for both the patient and physician. In other cases, it manifests as part of a spectrum of systemic anaphylaxis, which may be life-threatening. The disability and distress caused by urticaria can lead to serious impairment of quality of life, almost comparable to that experienced by patients with cardiovascular disease (1).
To further complicate the issue, a fairly extensive list of diseases can cause urticaria. Patients often seek medical attention with the hope that a reversible cause can be identified. Therefore, the challenge for the clinician is to try to identify a cause that could lead to a specific treatment or avoidance strategy (2). A carefully taken history, blood tests, cutaneous punch biopsy, and allergy skin testing may provide the clues to specific mechanisms in some cases. Often, however, it is impossible to pinpoint the exact cause. In such cases, judicious use of medications can ameliorate the condition and improve the patient's quality of life.
This article presents salient, practical, up-to-date information about diagnosis and management of this often frustrating disorder.
Diagnostic considerations
Urticaria is fairly easy to diagnose. It usually presents as raised, erythematous wheals accompanied by intense pruritus (figure 1: not shown). The lesions typically last a few hours, only to fade and reappear elsewhere. When urticarial lesions persist longer than 24 hours, a diagnosis of urticarial vasculitis or delayed pressure urticaria should be considered. In patients with urticarial vasculitis, the lesions appear to be indurated, and residual pigmentation is likely (figure 2: not shown).
In 50% of cases, lesions involve not only the dermis but also the subcutaneous or submucosal tissues, or both, resulting in angioedema (figure 3: not shown). Angioedema may affect the face, lips, tongue, or an extremity. It may be painful, owing to tissue distention, and can last for several days. Involvement of the respiratory tract can lead to stridor, and edema of the gastrointestinal tract can cause abdominal pain or intestinal obstruction. Patients who have both urticaria and angioedema tend to have more severe and persistent disease than patients with only one of the disorders.
Chronic urticaria is twice as common in women as in men. Although it occurs more often in adults, it can affect all age-groups. No racial predilection has been identified. Recently, an association between chronic urticaria and the major histocompatibility complex allele, HLA-DRB1*04, was identified. This association suggests that disease may involve an interaction between genes, the environment, and the immune system similar to that observed in asthma and coronary artery disease.
Several dermatologic disorders may mimic urticaria or present with urticarialike lesions. These include bullous pemphigoid, vasculitides, systemic lupus erythematosus (SLE), dermatitis herpetiformis, erythema multiforme, urticaria pigmentosa, and morbilliform drug eruptions (1). The patient history, specific morphologic characteristics of these lesions, and histopathologic findings in specific instances can help differentiate these conditions.
The causes of urticaria and angioedema are listed in table 1. Urticaria is unlikely in hereditary or acquired angioedema and angioedema due to angiotensin-converting enzyme (ACE) inhibitor therapy (3). Therefore, these diagnoses can be excluded in patients with both urticaria and angioedema.
Table 1. Causes of urticaria and angioedema
IgE-mediated factorsIngested or injected allergens (eg, food, drugs, Hymenoptera venom, transfusion reactions)Anti-IgE antibodyLatex Complement-mediated factorsC3b-inactivator deficiencyHereditary or acquired angioedema*Urticarial vasculitisSerum sickness Direct mast cell-releasing agentsOpiatesRadiocontrast mediaCurare, tubocurarine chloride Agents that alter arachidonic acid metabolismAspirinNonsteroidal anti-inflammatory drugsSelected cyclooxygenase-2 inhibitors Physical stimuliDermatographismHeat and coldVibrationContact with water (aquagenic)PressureExposure to ultraviolet or visible light (solar)Exercise-induced (cholinergic) Autoimmune mast cell diseaseIgG anti-IgE antibodiesIgG anti-Fc(epsilon)RI antibodies Idiopathic urticaria OtherFood additives (eg, dyes, benzoates)Angiotensin-converting enzyme inhibitors* Fc(epsilon)RI, high-affinity receptor for IgE on mast cells. *Patient is more likely to present with angioedema alone than with urticaria.
Classification
Urticaria may be classified as either acute or chronic.
Acute urticaria
Typically, lesions lasting less than 6 weeks are referred to as acute urticaria. This form is more common in young people and is most likely due to exposure to food allergens (eg, nuts, eggs, fish, shrimp), food additives (eg, tartrazine dyes, benzoic acid derivatives [sodium benzoate, 4-hydroxybenzoic acid]), certain medications (eg, aspirin, nonsteroidal anti-inflammatory drugs [NSAIDs]), or radiocontrast media. Antibiotics (eg, penicillins, sulfonamides) may produce acute urticaria by either IgE- or IgG-mediated mechanisms (Arthus phenomenon). Patients with aspirin sensitivity can present with either mucosal reactions (the aspirin triad of nasal polyposis, sinusitis, and asthma) or cutaneous reactions (urticaria or anaphylaxis). Moreover, up to 40% of patients with urticaria may have a flare on ingestion of aspirin or an NSAID. Careful history taking and physical examination often reveal the diagnosis of acute urticaria.
Chronic urticaria
Chronic urticaria is most common in middle-aged women. In spite of a careful search, a causative agent is discovered in less than 25% of cases; the remainder are labelled chronic idiopathic urticaria. Specific disorders that have a known association with chronic urticaria include fungal infection (with Candida albicans), parasitic or bacterial infection (eg, sinus, urinary tract, dental), viral hepatitis B or C, connective tissue diseases (ie, SLE and Sjögren's syndrome), malignant disease, physical stimuli, and sensitivity to certain medications (eg, NSAIDs, aspirin) or food additives. SLE and Sjögren's syndrome are usually associated with urticarial vasculitis. Although less than 10% of patients with chronic urticaria have sensitivity to food additives, appropriate testing and elimination of the suspected additive from the diet can have a quieting effect on the disorder.
To further complicate matters, chronic idiopathic urticaria is likely to coexist with the physical urticarias (eg, cold urticaria, pressure urticaria) (4). Moreover, patients with chronic idiopathic urticaria have a higher incidence of autoimmune thyroid disease than those with acute urticaria. Relapse is more likely in chronic urticaria, and this can be frustrating to patient and physician alike. Only 50% of cases are likely to remit within 1 year, and up to 40% of cases lasting longer than 6 months are likely to persist for 10 years or more (4).
Urticarial syndromes
Before a diagnosis of chronic idiopathic urticaria is made, several specific urticarial syndromes need to be considered and excluded: autoimmune mast cell disease, urticarial vasculitis, physical urticaria, and exercise-induced urticaria.
Autoimmune mast cell disease: The term "autoimmune mast cell disease" is derived from recent descriptions of an auto-antibody that has histamine-releasing properties and has been found in the serum of some patients with chronic urticaria (4). The autoantibody belongs to the IgG class and induces histamine release from both peripheral blood basophils and tissue-derived mast cells. The incidence of autoimmune mast cell disease in patients with chronic urticaria ranges from 25% to 48%.
It now appears that two distinct types of autoantibodies may be found circulating in affected patients. One is directed toward the high-affinity receptor for IgE [Fc(epsilon)RI] that is found on the surface of mast cells and basophils. By attaching to and cross-linking with this receptor, the antibody allows the elaboration of mast cell mediators that can then recruit inflammatory cells and lead to the development of urticarial lesions (see box below). The other type of antibody is directed against IgE itself rather than toward the receptor, leading to an IgE-anti-IgE immune complex that can activate mast cells. The presence of a circulating antibody directed against Fc(epsilon)RI can be detected on intradermal testing with autologous serum (serum obtained from the same patient); a positive reaction leads to wheal formation (4). Another test detects release of histamine from blood basophils in response to serum of patients with these circulating antibodies. Additional evidence of autoimmune predisposition in chronic urticaria is the high incidence of autoimmune thyroid disease (Hashimoto's thyroiditis) in affected patients.
Management of autoimmune mast cell disease is the same as that of chronic idiopathic urticaria, except that in patients who have severe disease, treatment with plasmapheresis, intravenous immune globulin, or cyclosporine (Neoral, Sandimmune, SangCya) to remove or suppress autoantibody formation may be a consideration.
Urticarial vasculitis: Differentiating between chronic idiopathic urticaria and urticarial vasculitis is important because therapeutic approaches to the two disorders may be different. Urticarial vasculitis is characterized by vasculitic changes seen on biopsy (2,5,6). It is more common in women than in men, and it usually presents in the fourth decade of life (7). Typically, urticarial vasculitis is characterized as follows:
· Lesions are described as painful, burning, pruritic, or all of these.
· Lesions show central clearing or have a dusky discoloration. Diascopy causes the erythematous halo to disappear and reveals the unapparent purpura as a dark red or brown macule in the center of the blanched lesion (8).
· Individual lesions last longer than 24 hours.
· Residual pigmentation of the lesions is seen.
· Associated systemic symptoms (eg, arthralgias, fever, uveitis, episcleritis, hematuria, wheezing, chest pain, diarrhea) may occur. In a study of 72 cases of urticarial vasculitis, Mehregan and colleagues (5) noted the following symptoms: angioedema in 30 patients (42%), arthralgias in 35 (49%), obstructive lung disease in 15 (21%), abdominal or chest pain in 12 (17%), fever in 7 (10%), Raynaud's phenomenon in 4 (6%), and episcleritis or uveitis in 3 (4%). Pleural effusions also have been described (9).
Urticarial vasculitis may be a primary disorder or a secondary effect of various underlying conditions, such as sulfite sensitivity, connective tissue disorders (SLE, Sjögren's syndrome, cryoglobulinemia), infection (hepatitis B or C, infectious mononucleosis, Coxsackie B virus infection), iatrogenic disorders (sensitivity to BCG vaccine [TICE BCG], procainamide hydrochloride [Procanbid, Pronestyl], herbal medication), Schnitzler's syndrome (eg, urticarial vasculitis associated with an IgM paraprotein), paraneoplastic syndrome (colonic adenocarcinoma), and familial cold urticaria (7,9-14). Histopathologic findings include swelling of endothelial cells, neutrophilic perivascular infiltration, extravasation of erythrocytes, leukocytoclasis (nuclear dust), and fibrinoid deposits around blood vessels (5). Hemorrhage and edema of the dermis may also occur.
The prognosis varies, depending on whether the diagnosis is normocomplementemic urticarial vasculitis syndrome (NUVS) or hypocomplementemic urticarial vasculitis syndrome (HUVS) (5,15). NUVS is more benign than HUVS, but both disorders are rarely fatal (7). Patients with HUVS are likely to have an elevated erythrocyte sedimentation rate, low or undetectable levels of C1q, and elevated levels of antibodies to C1q protein, and half are likely to have a positive antinuclear antibody test (5,15). Affected patients are also more likely to have pericardial effusions, arthralgias, abdominal pain, chronic obstructive pulmonary disease, and deposition of immunoglobulins or complement component C3, or both, in blood vessels and basement membranes (5).
Physical and exercise-induced urticarias: Urticaria can be precipitated in some persons after exposure to physical stimuli, such as cold, pressure, vibration, contact with water (aquagenic) or visible light (solar), and exercise (cholinergic). Dermatographism is common and is provoked by gentle stroking of the skin. Physical urticarias can be induced in susceptible persons by provocative testing, such as application of an ice pack for 10 minutes, application of pressure, exposure to radiation, a hot shower, and strenuous exercise (4,16). In cholinergic urticaria, punctate wheals associated with flushing occur in response to raised core body temperature within minutes after the start of exercise (16). A subset of patients may eventually present with exercise-induced anaphylaxis characterized by vascular collapse.
Diagnostic evaluation
Certain facts should be kept in mind during evaluation of patients with suspected urticaria. First, the disorder is very often benign and self-limited. Second, acute urticaria is often due to infection, a new medication, or a specific food; thorough history taking and specialized testing can lead to the correct diagnosis. In contrast, chronic urticaria is more likely to elude definitive diagnosis. Nevertheless, laboratory tests (eg, measurement of complete blood cell count, erythrocyte sedimentation rate, serum chemistry values, complement C3 and C4, thyrotropin level) should be performed to exclude systemic disease. Specific allergy or provocative tests (eg, additive challenge, exercise, pressure, cold) may be required to further clarify the diagnosis. In some cases, tests for antinuclear antibodies and hepatitis, as well as skin tests for food and latex sensitivities, are indicated.
Punch biopsy of an urticarial lesion often provides useful information that can help guide management. A 4-mm cutaneous punch biopsy may reveal findings indicative of urticaria, can help rule out conditions that mimic urticaria, and generally can help distinguish urticaria from urticarial vasculitis. Biopsy of urticarial lesions reveals inflammation. Various reports have shown the inflammatory response to be sparse or dense; predominantly lymphocytic, neutrophilic, or mixed; and perivascular or both perivascular and interstitial. For the most part, these histologic differences have no clinical correlations. Some of the differences may represent the timing of the biopsy (17) or the intensity of the urticarial stimulus (18). According to Ackerman (19), perivascular neutrophils and eosinophils are typically seen in early lesions, perivascular lymphocytes and interstitial neutrophils and eosinophils in fully developed lesions, and sparse perivascular lymphocytes and a few eosinophils in late lesions (figure 4: not shown). Interestingly, no consistent histopathologic differences between patients with and patients without antibodies to the high-affinity IgE receptor on mast cells have been noted on standard light microscopy (20).
In contrast, biopsy of urticarial vasculitis lesions usually shows changes typical of leukocytoclastic vasculitis, including fibrinoid deposition in vessels and a neutrophilic infiltrate with nuclear dust (figure 5: not shown). Some reports (9,21) have suggested that lesions of urticarial vasculitis show more eosinophils and less extravasation and nuclear dust than lesions of other types of leukocytoclastic vasculitis. Biopsy in patients with HUVS often shows a diffuse neutrophilic infiltrate (5,9,21). However, early lesions of urticarial vasculitis may have features of urticaria rather than leukocytoclastic vasculitis (22).
Management
Patient education, avoidance of known triggers, and pharmacotherapy each has a crucial role in the management of urticaria and urticarial vasculitis.
Patient education
Patients with urticaria need to be educated about their disease and given specific instructions on crisis management. If a patient has angioedema or a tendency toward anaphylaxis, an injectable epinephrine preparation (Ana-Guard, EpiPen) needs to be provided for emergency use.
Avoidance of triggers
When a specific trigger (eg, latex, a food or food additive) has been identified, the patient must avoid any exposure to it. Treatment with medications known to trigger urticaria and angioedema, such as ACE inhibitors, aspirin, and NSAIDs, should be discontinued and alternatives provided.
Pharmacotherapy
Patients with persistent urticaria in spite of elimination of potential triggers are candidates for pharmacotherapy (table 2). Drug therapy leads to satisfactory control in most cases.
Table 2. Selected medications useful in management of urticaria and angioedema
Agent Dosage Formulation US FDApregnancycategory* Indications

H1 RECEPTOR ANTAGONISTS

Cetirizine HCl (Zyrtec) Adults: 10-20 mg/day Tablet B Chronic idiopathic urticaria, urticarial vasculitis, angioedema
Children 2-6 yr: 2.5-5 mg/day, >6 yr: 5-10 mg/day Liquid

Loratadine (Claritin) Adults: 10 mg/day Tablet, rapidly disintegrating tablet B Chronic idiopathic urticaria, urticarial vasculitis, angioedema
Children >6 yr: 5-10 mg/day Liquid

Fexofenadine HCl (Allegra) Adults: 120 mg/dayChildren 6-11 yr: 30 mg bid Capsule, tablet C Chronic idiopathic urticaria, urticarial vasculitis, angioedema

H2 RECEPTOR ANTAGONISTS

Cimetidine (Tagamet) 300 mg qid Tablet, liquid B Chronic idiopathic urticaria, angioedema

Ranitidine HCl (Zantac) 150 mg bid Tablet, capsule, liquid, injection B Chronic idiopathic urticaria, angioedema

TRICYCLIC ANTIDEPRESSANTS

Amitriptyline HCl (Elavil) 10-100 mg/day Tablet, injection D Chronic idiopathic urticaria, angioedema

Doxepin HCl (Sinequan) 10-100 mg/day Capsule, oral concentrate C Chronic idiopathic urticaria, angioedema

LEUKOTRIENE RECEPTOR ANTAGONISTS

Montelukast sodium (Singulair) Adults: 10 mg/day Children >6 yr: 5 mg/day Tablet B ?Chronic idiopathic urticaria, aspirin sensitivity

Zafirlukast (Accolate) Adults: 20 mg bid Children >6 yr: 10 mg bid Tablet B ?Chronic idiopathic urticaria, aspirin sensitivity

OTHER

Colchicine 0.6 mg bid Tablet C Urticarial vasculitis

Dapsone 50-150 mg/day Tablet C Urticarial vasculitis

Epinephrine Injection C Angioedema, anaphylaxis
• Ana-Guard (1:1,000) Adults: 0.3 mL/dose SCChildren: 0.01 mL/kg/dose SC
• EpiPen (1:1,000) Adults: 0.3 mg/dose
• EpiPen Jr (1:2,000) Children <12 yr: 0.15 mg/dose

Albuterol (Proventil, Ventolin) Adults: 2-4 mg qid Children 6-12 yr: 2 mg qid Tablet, liquid C Angioedema, anaphylaxis

FDA, Food and Drug *****istration. *FDA pregnancy categories: A, controlled studies show no risk; B, no evidence of risk in humans; C, risk cannot be ruled out; D, positive evidence of risk; X, contraindicated in pregnancy.

Traditional antihistamines, such as hydroxyzine (Atarax, Vistaril), cyproheptadine hydrochloride (Periactin), and azatadine maleate (Optimine), can be very effective interventions. However, their use is associated with many intolerable side effects, including drowsiness and dry mouth. The newer-generation antihistamines, such as cetirizine hydrochloride (Zyrtec), loratadine (Claritin), and fexofenadine hydrochloride (Allegra), have a rapid onset of action, are very effective, and have minimal adverse effects (table 2). Loratadine and cetirizine are relatively safe for use by pregnant women and are available in liquid formulations for pediatric use.
In some patients, histamine1 (H1) receptor antagonists alone are ineffective and may have to be combined with a histamine2 (H2) receptor antagonist, such as cimetidine (Tagamet) or ranitidine hydrochloride (Zantac). Alternatively, tricyclic antidepressants, such as doxepin hydrochloride (Sinequan) or amitriptyline hydrochloride (Elavil), may be used. These agents have properties of both H1 and H2 receptor antagonists but should be given at bedtime because of their high potential for sedation. They should be used with caution in patients with glaucoma or genitourinary tract obstruction. In some patients, especially those with aspirin-sensitive urticaria, leukotriene receptor antagonists may be beneficial (23).
If angioedema is a major component, the patient should be provided with an epinephrine autoinjector (EpiPen) for use in the event of respiratory distress. In resistant cases, other therapeutic options, including beta-adrenergic drugs (eg, terbutaline sulfate [Brethaire, Brethine, Bricanyl]) and calcium channel blockers (eg, nifedipine [Adalat, Procardia]), have been reported to be somewhat successful. Thyroid hormone replacement therapy is beneficial in some patients with autoimmune thyroid disease. Patients with autoimmune mast cell disease are treated the same way as patients with chronic urticaria, except that in severe cases, plasmapheresis, cyclosporine therapy, and intravenous immune globulin infusions may be used to remove the autoantibody or suppress its formation.
In patients with a mild form of urticarial vasculitis syndrome, antihistamines or brief courses of a corticosteroid, such as prednisone, are effective therapy. In more severe cases, prednisone is usually *****istered in a tapering schedule. Occasionally, a patient has difficulty metabolizing prednisone to prednisolone and requires methylprednisolone (Medrol) for efficacy. Urticarial vasculitis also responds to indomethacin (Indocin), hydroxychloroquine (Plaquenil) sulfate, or colchicine or dapsone *****istered in the dosage schedule shown in table 2 (9). If dapsone is *****istered, glucose-6-phosphate dehydrogenase (G6PD) levels must be measured to avoid the possibility of dapsone-induced hemolytic anemia, which can be severe.
If severe systemic disease accompanies urticarial vasculitis, treatment with prednisone (1 mg/kg of body weight) should be initiated with an attempt to taper the dose slowly. If adverse effects with corticosteroid therapy are excessive, the use of steroid-sparing agents, such as azathioprine (Imuran) and cyclophosphamide (Cytoxan, Neosar), may be considered. In some cases, plasma exchange has been used (9). The roles of cyclosporine, intravenous immune globulin, and monoclonal antibody therapy in urticarial vasculitis need to be assessed (9).
Summary
Urticaria and angioedema are common dermatologic problems seen by primary care physicians. A carefully taken history, physical examination, specific tests, and skin biopsy often provide useful diagnostic information. In patients with chronic urticaria, urticarial vasculitis and diseases that mimic urticaria need to be ruled out. A variety of treatment options are available for patients with urticaria and urticarial vasculitis. Pharmacologic therapy is useful when the specific cause is undetermined. When a trigger has been identified, the patient must avoid exposure to it. Patient education is an important component of management and should include instructions on crisis management, particularly for patients who have angioedema or a tendency for anaphylaxis.
References
1. Kanwar AJ, Greaves MW. Approach to the patient with chronic urticaria. Hosp Pract (Off Ed) 1996;31(3):175-89
2. Mukkamala R, Baban N, Krishnaswamy G, et al. Persistent urticarial eruption in an asthmatic patient. Ann Allergy Asthma Immunol 1996;77(5):359-64
3. O'Hollaren MT, Porter GA. Angiotensin converting enzyme inhibitors and the allergist. Ann Allergy 1990;64(6):503-6
4. Greaves MW. Chronic urticaria. N Engl J Med 1995;332(26):1767-72
5. Mehregan DR, Hall MJ, Gibson LE. Urticarial vasculitis: a histopathologic and clinical review of 72 cases. J Am Acad Dermatol 1992;26(3 Pt 2):441-8
6. Bishop PC, Wisnieski JJ, Christensen J. Recurrent angioedema and urticaria. West J Med 1993;159(5):605-8
7. Venzor J, Baer SC, Huston DP. Urticarial vasculitis. Immunol Allergy Clin North Am 1995:15(4):761-74
8. Dahl MV. Clinical pearl: diascopy helps diagnose urticarial vasculitis. J Am Acad Dermatol 1994;30(3):481-2
9. Black AK. Urticarial vasculitis. Clin Dermatol 1999;17(5):565-9
10. Laman SD, Provost TT. Cutaneous manifestations of lupus erythematosus. Rheum Dis Clin North Am 1994;20(1):195-212
11. Misery L, Combemale P. BCG-vaccine-induced lupus vulgaris and urticarial vasculitis. (Letter) Dermatology 1993;186(4):274
12. Wuthrich B, Kagi MK, Hafner J. Disulfite-induced acute intermittent urticaria with vasculitis. Dermatology 1993;187(4):290-2
13. Morita A, Sakakibara S, Yokota M, et al. A case of urticarial vasculitis associated with macroglobulinemia (Schnitzler's syndrome). J Dermatol 1995;22(1):32-5
14. Daoud MS, Gibson LE, Daoud S, et al. Chronic hepatitis C and skin diseases: a review. Mayo Clin Proc 1995;70(6):559-64
15. Wisnieski JJ, Baer AN, Christensen J, et al. Hypocomplementemic urticarial vasculitis syndrome. Clinical and serologic findings in 18 patients. Medicine (Baltimore) 1995;74(1):24-41
16. Volcheck GW, Li JT. Exercise-induced urticaria and anaphylaxis. Mayo Clin Proc 1997;72(2):140-7
17. Winkelmann RK. Immunofluorescent and histologic study of cold urticaria. Arch Dermatol Res 1985;278(1):37-40
18. Winkelmann RK, Reizner GT. Diffuse dermal neutrophilia in urticaria. Hum Pathol 1988;19(4):389-93
19. Ackerman AB. Histologic diagnosis of inflammatory skin diseases. In: Ackerman AB, Chongchitnant N, Sanchez J, et al, eds. Histologic diagnosis of inflammatory skin diseases: an algorithmic method based on pattern analysis. 2nd ed. Baltimore: Williams & Wilkins, 1997:771-2
20. Sabroe RA, Poon E, Orchard GE, et al. Cutaneous inflammatory cell infiltrate in chronic idiopathic urticaria: comparison of patients with and without anti-Fc(epsilon)RI or anti-IgE autoantibodies. J Allergy Clin Immunol 1999;103(3 Pt 1):484-93
21. Davis MD, Daoud MS, Kirby B, et al. Clinicopathologic correlation of hypocomplementemic and normocomplementemic urticarial vasculitis. J Am Acad Dermatol 1998;38(6 Pt 1):899-905
22. Kano Y, Orihara M, Shiohara T. Time-course analyses of exercise-induced lesions in a patient with urticarial vasculitis. Australas J Dermatol 1996;37(Suppl 1):S44-5
23. Bensch G, Borish L. Leukotriene modifiers in chronic urticaria. Ann Allergy Asthma Immunol 1999;83(4):348

Pathogenic pathways of urticaria
Cutaneous punch biopsy of urticarial lesions may show dilatation of venules, edema, mast cell degranulation, and infiltration of mononuclear cells or eosinophils or both. Cellular infiltration is absent in acute urticarial lesions, but chronic urticaria is characterized by perivascular lymphocytic infiltration. The mast cell is the major effector cell in urticaria and is capable of being degranulated by allergens and other diverse stimuli, including neuropeptides, complement activation products, radiocontrast media, and certain medications (1).
Mast cell degranulation may involve the elaboration of products of arachidonic acid metabolism (eg, leukotrienes, prostaglandins), histamine, and inflammatory cytokines (eg, tumor necrosis factor-alpha, interleukins IL-3 and IL-5, chemokine IL-8) (2,3). Release of these mediators leads to vasodilatation, increased vascular permeability, endothelial activation, and the recruitment of inflammatory cells such as neutrophils, eosinophils, and T cells (eg, CD4+ or CD8+ cells that are arranged in a perivascular location). This response is mediated by adhesive interactions between infiltrating cells and endothelium, which involve cell adhesion molecules such as intercellular adhesion molecule 1 (ICAM-1), E-selectin, and vascular cell adhesion molecule 1 (VCAM-1). Infiltrating cells (eg, CD4+ T cells) are further activated by contact with antigen, express the activation marker HLA-DR, and elaborate inflammatory mediators (4,5). Accordingly, serum levels of mast cell-derived and mononuclear cell-derived mediators such as histamine, prostaglandins, and chemotactic proteins are elevated in patients with certain forms of urticaria following antigen challenge (4).
Therapeutic options for the urticarial syndromes include treatment with histamine1 and histamine2 receptor blockers, leukotriene blockers, dapsone or colchicine, cyclosporine, or glucocorticoids; antibody removal by plasmapheresis; and avoidance of triggering agents and allergens.
References
1. Costa JJ, Weller PF, Galli SJ. The cells of the allergic response: mast cells, basophils, and eosinophils. JAMA 1997;278(22):1815-22
2. Krishnaswamy G, Lakshman T, Miller AR, et al. Multifunctional cytokine expression by human mast cells: regulation by T cell membrane contact and glucocorticoids. J Interferon Cytokine Res 1997;17(3):167-76
3. Bressler RB. Pathophysiology of chronic urticaria. Immunol Allergy Clin North Am 1995;15(4):659-77
4. Leung DY, Diaz LA, DeLeo V, et al. Allergic and immunologic skin disorders. JAMA 1997;278(22):1914-23
5. Greaves MW. Chronic urticaria. N Engl J Med 1995;332(26):1767-72

Dr Krishnaswamy is chief, division of allergy and immunology, James H. Quillen Veterans Affairs Medical Center, and associate professor, department of medicine, East Tennessee State University, Johnson City. Dr Youngberg is associate chief of staff for research, James H. Quillen Veterans Affairs Medical Center, and professor, department of pathology, East Tennessee State University. Correspondence: Guha Krishnaswamy, MD, Department of Medicine, PO Box 70622, East Tennessee State University, Johnson City, TN 37614-0622