Urticaria

PV S Prasad

 Department of Dermatology, Raiah Muthiah Medical College & Hospital, Annamalai University, Annamalai Nagar-608 002, India

Correspondence Address:
PV S Prasad
Department of Dermatology, Raiah Muthiah Medical College & Hospital, Annamalai University, Annamalai Nagar-6008 002
India

Definition

The term urticaria is defined as a transient eruption of circumscribed edematous and usually itchy swellings of the dermis.[1] The other names given are nettle rash, hives or weals.[2] These lesions last for a few hours but not exceeding 48 hours. The term angioneurotic oedema denotes similar but larger swellings of the deep dermal, sub-cutaneous and sub mucosal tissues. The other names are angioedema, giant urticaria and Quinke′s oedema.[2] Urticaria and angio-oedema are important components of systemic anaphylaxis which is an acute life threatening condi-tion.[2] Several well illustrated monographs are avail-able on urticaria which may be referred for details.[1],[3],[4]

Classification[1],[2],[3],[4]

Urticaria may be broadly classified on the basis of duration and trigger factors. It is classified into ′acute′ and ′chronic′ on the basis of duration. This is an arbitrary division and is between 6 weeks to 8 weeks. Acute urticaria is diagnosed retrospectively with a history of less than 6-8 weeks duration. The causative factor is easily identified in acute urticaria whereas it is difficult in chronic urticaria. When there is no detectable cause in chronic urticaria it is also known as chronic idiopathic urticaria.[5] Recently stud-ies after thorough examination of patients with chronic idiopathic urticaria revealed that 30% had Ig G autoantibodies against the Ig E receptor.[6]

Immune complex urticaria comprises of se-rum sickness and urticarial vasculitis,[7] both of which are classical examples of Type III immunological re-action. Papular urticaria is the result of hypersensi-tivity to bites from certain insects like mosquitoes, gnats, fleas, mites and beg bugs. Physical urticarias are triggered by various physical agents like heat, cold, pressure, sunlight and water. In all these, the physical stimulus induces reproducible wealing.[8],[9]

Pathogenesis

Activation of cutaneous mast cells liberates various mediators predominantly histamine which induces increased permeability of capillaries and venules which in turn produces uriticaria. The clini-cal response of urticaria to antihistamines proves this hypothesis.[1],[2] Mast cells may be activated by allergic or non-allergic mechanisms. Allergic mast cell acti-vation occurs as a result of linkage of two adjacent a sub - units of high affinity eg. penicillin. As a result of this, preformed histamines, proteases, prostag-landin D2, LT4 and interleukin 4 (IL-4), IL - 8 and tumour necrosis factor (TNF - a) are released. Non allergic mast cell activation occurs with a variety of substances like neuropeptides (substance P), drugs like morphine, codeine, vancomycin, radio contrast media and some foods such as strawberries.[1],[2]

Chronic idiopathic urticaria patients can de-velop Ig G antibodies directed against the sub unit of the FCE RI or against the receptor bound Ig E.[6],[10],[11] Immune modulating therapy like plasmapheresis[12] and intravenous immunoglobulin[13] were associated with remission in some patients. Thus, in 30% of patients with chronic idioapathic urticaria, an autoim-mune mechanism could play a role.

Histamine can stimulate sensory afferent nerves to release substance P as these are situated close to the mast cells. This stimulates further re-lease of mast cell histamine and also expression of various adhesion molecules like P selectin and E selectin which amplifies wealing reaction.[2]

Interleukins like IL-4 regulates vascular en-dothelial adhesion molecules whereas, IL - 8 causes neutrophil leukocyte accumulation. IL-4 also stimu-lates T - lymphocyte differentiation and immunoglo-bulin production. However a direct role of these interleukins has not been found.[2],[14],[15]

Plasma derived mediators such as bradykinin and complement have no role in chronic urticaria. However, bradykinin plays a role in production of angio-oedema. Complement activation occurs in ur-ticarial vasculitis and immune complex urticaria. Lym-phocytes, neutrophils and eosinophils also may re-lease a variety of cytokines which may enhance or perpetuate the weal response. This mechanism is demonstrated by their presence in the venous efflu-ent from physical urticarias like cold, cholinergic and solar urticarias.[2] Increased substance P and vasoac-tive intestinal peptide (VIP) have been demonstrated in cold and cholinergic urticarial lesions. Urticarial vasculitis, also called hypocom- plementaemic vas-culitis, resembles systemic lupus erythematosus in its pathogenesis.[16] However it may also involve ab-normal genetic immunoregulation in some.[17]

Papular urticaria is due to type I and type IV hypersensitivity reaction but the antigen remains undetermined.[18]

Prevalence

The exact figures are lacking from many coun-tries but it is not an uncommon condition. Sheldon reported an incidence of 15%[19] and the prevalence is reported as 0.1% by Hellgren.[20] More than one fifth of the population suffer at one time. 60% of patients are in the age group of 20-40 years. Inci-dence is higher in older age group.[1]

Clinical features[1],[2],[3]

Each episode starts with itching. Following this, erythematous macules and weals appear which are transient and disappear within a few hours to a maximum of 24 hours. The weals may vary in size ranging from a few millimeters to many centimeters. The weals appear on any part of the body and may be associated with angio-oedema. The skin lesions resolve without any trace. Eventhough many patients claim worsening of the lesions during full moon and new moon days there is no convincing evidence for this. Inspite of severe pruritus there are no scratch marks in urticaria as the patients tend to rub the skin. Urticaria occasionally may be associated with a few systemic symptoms such as vomiting, giddiness, malaise, headache, abdominal pain, diarrhoea, diz-ziness and rarely anaphylaxis.[21] Premenstrual exacerbation may be noticed in some.

Causes of urticaria

1. DrugsMany drugs cause urticaria through allergic or non allergic mechanisms.[22],[23] Drugs produce acute urticarial reactions usually within 36 hours of admin-istration.[2] Penicillins, cephalosporins, sulfonamides and tetracyclines are some examples of drug - in-duced urticaria. Acetyl salicylic acid and non steroi-dal anti inflammatory drugs are responsible to pro-duce urticaria through allergic mechanism.[24] Drug which is taken for a long time is unlikely to cause urticaria. On the contrary even a small quantity of penicillin present in the dairy products may produce severe urticaria in a sensitive person.[25]

2. InfectionsInfections may produce either acute or chronic urticaria.[22],[23],[26] Non specific infections may be respon-sible for acute urticaria.[26] Hepatitis B viral infection, streptococcal throat infection, and Campylobacter jejuni are a few examples which can produce acute urticaria. Bacterial infections of the dental, throat, respiratory, urinary tracts and gall bladder rarely may be responsible for chronic urticaria. The urticarial lesions do not alter with treatment of underlying chronic infection.[2]′[7] Tebbi et al stressed the role of Helicobacter pylori in chronic urticaria.[28]

3. InfestationsGastro-intestinal parasites were thought to be commonly responsible to cause urticaria. Ankylos-toma, strongyloides, echinococcus and Toxacara canis are few examples. However this has become a rare cause as shown in recent Indian studies.[29] Ascariasis produces urticaria through allergic mechanism while the other intestinal parasites produce the lesions through non allergic mechanism.

4. InhalantsVarious substances like grass, pollens, mould, spores, animal danders, and house dust may cause acute or chronic urticaria.[30]

5. IngestionFood and food additives can cause both acute and chronic urticaria. Fish, milk, peanut, beans, po-tato, rice, carrot and drumstick are responsible for acute urticaria mediated through IgE dependant mechanism.[31] The reaction can occur in a few min-utes to many hours. Though a variety of foods are attributed to produce urticaria a double blind chal-lenge reproduced the lesions only in some.[31] Among the alcoholic beverages red wine may cause urti-caria in some.

6. Insect bitesPapular urticaria occurs through the bite of insects most commonly mosquitoes and bed bugs. These are chronic and recurrent. On the contrary bee or wasp stings (hymenoptera) may produce se-vere acute urticaria or anaphylaxis through allergic mechanism which may be life threatening.[32]

7. InjectionsParenteral injection of therapeutic sera pro-duces serum sickness through complement mediated Type III reactions.[7]

8. ImplantDental prosthesis and metal pins used in or-thopaedics practice may rarely cause urticaria.[2]

9. Systemic diseaseSystemic lupus erythematous produces urti-carial vasculitis more commonly than chronic urticaria. Increased incidence of patients with thyroid auto antibodies have been reported and treatment with thyroxine can result in clinical remission in some.[33],[34]

10. OthersPsychological stress may favour urticaria[31] whereas depression decreases the threshold for pru-ritus.[36] In young children, cows milk can produce allergy.

Differential diagnoses

More often persistent erythemas and purpuras have to be differentiated from urticaria. These le-sions last longer than 24 hours whereas urticarial weals resolve by that time.[37] Erythema multiforme and early vesico bullous eruptions have also to be distinguished from urticaria.[2]

Prognosis[5]

In a follow up study by Champion at London in 554 patients 50% still had active disease after 6 months. Of these patients 40% continued to have intermittent symptoms 10 years later. The prognosis worsened in patients with angio-oedema.

Investigations

Routine hematological investigations are to be carried out in all patients. Erythrocyte sedimen-tation rate (ESR) if high may reflect on occult infec-tion. Repeated microscopic examination of the stools may reveal an unusual intestinal parasite. Other in-vestigations are done according to symptomatology. If history does not reveal a cause investigations rarely provide an answer either in acute or chronic urti-caria.[2] If weals persist and are painful, with the pres-ence of systemic symptoms, a skin biopsy may be done to rule out urticarial vasculitis. Screening tests for thyroid functions may reveal an abnormality in 7% of patients with chronic urticaria.[2] Extensive bio-chemical tests, total IgE levels and RAST are not indicated[27] routinely. Intracutaneous or epicutaneous tests are less helpful.[5]

Urticarial vasculitis

In urticarial vasculitis the clinical lesions re-semble urticaira and the histological features re-semble vasculitis. The histopathology reveals a typi-cal necrotizing vasculitis of the small venules with deposition of immunoglobulin and complement. In patients with low serum complement (hypo complementemic vasculitis) neutrophils predominate whereas in the other group lymphocytic infiltrate is more typical.[38] The lesion demonstrates histologi-cal changes ranging from a sparse inflammatory in-filtrate to dense infiltrate and finally vasculitis.[39]

The cutaneous lesions of urticarial vasculitis resemble chronic idiopathic urticaria but feels firmer and lasts for more than 24 hours. These lesions leave an ecchymotic area due to extravasation of red blood cells on clearing. Systemic symptoms are common. More than 50% of cases have arthralgia. In another 20% gastro intestinal symptoms like nausea and vomiting may be associated. Angio-oedema may be present in 40% of cases.[38] Urticarial vasculitis is a Type III hypersensitive reaction suggested by the presence of circulatory immune complexes and depo-sition of immunoglobulin and complement in the ves-sel walls. Viral infections like hepatitis B and C, Epstein-Barr virus and Borrelis burgodoeferi, serum sickness, collagen vascular disease, hypergamma globulinemia, drugs like cimetidine, diltiazem and hematological diseases are the causes of urticarial vasculitis. However no definite etiology can be found in majority of the cases.[2] Laboratory abnormalities include raised ESR and reduced complement levels. Auto antiboides may be present and there may be evidence of renal damage. The disease has a benign course lasting for 3 years.[38]

Papular urticaria

This results from hypersensitivity to bites from certain insects such as mosquitoes, gnats, fleas, mites and beg bugs. It is common in childhood. It is char-acterized by symmetrically distributed pruritic pap-ules and papulovesicles. Pruritus may give rise to secondary pyoderma. Skin lesions occur in crops. His-topathology shows perivascular and periadnexal eosi-nophilic infiltrate. Type I hypersensitivity plays a role in the pathogenesis but the antigen remains unde-termined.[20]

Physical urticarias

In this type of urticaria the physical stimulus induces a reproducible wealing.[2] Physical urticarias amount to 19% of patients with urticarias.[40] Dermog-raphism and cholinergic urticarias are the common types of physical urticarias. Physical urticarias can give rise to angio-oedema if the stiumulus is suffi-ciently great or if the patient is sensitive.[2]

Dermographism

This is also called as factitious urticaria which involves the weal flare phenomenon of triple response of Lewis.[41] This is elicited by firm stroking of the skin at a pressure of less than 36 g/mm2 which induces erythema due to capillary vasodilatation followed by oedema and a surrounding flare.[42] If this physiologi-cal response is exaggerated, persists and the pa-tient has itching then it is called as ′symptomatic dermographism′. In some patients stroking the skin is followed by only itching and not wealing. The symp-toms are milder. This is called as ′simple dermogra-phism′.[43] Dermographism is idiopathic in nature. There is no correlation between food allergy and der-mographism.[43] Rarely penicillin reaction may cause this.[44] The incidence of dermographism is not in-creased in patients with chronic idiopathic urticaria. Cholinergic urticaria may be associated with ′cholin-ergic dermographism′.[45] In ′red dermographism′ repeated rubbing is necessary to produce weals.[46] In ′delayed dermographism′ the immediate response will fade away which may be followed by a late response which persists for more than 48 hours.[47] ′White der-mographism′ is due to capillary vasoconstriction which occurs in atopics. Pressure from a metallic object on the skin may give rise to discoloration which is termed as ′black dermographism′.

Delayed pressure urticaria

In this type, sustained pressure applied to the skin produces wealing within half-an-hour to 10 hours. The lesion may last from few hours to few days.[48] This is usually associated with chronic ordi-nary urticaria.[48] The mechanism of this condition is not known and no allergen has been identified. The cellular changes point to an up-regulation of vascu-lar adhesion molecules like E-selectin. The process may be amplified by IL-6 and fibrin present in le-sions.[49] Weals occur under areas of pressure. Lesions are itchy or tender and painful when it may mimic urticarial vasculitis. The lesions may be reproduced by applying 7kg weights for 15 minutes over the shoulder.[50] Delayed pressure urticaria may sponta-neously resolve after many years.

Cholinergic urticaria

This is a distinctive type of urticaria where small weals appear associated with itching in response to exercise and sweating. Acetylcholine can release histamine which is responsible for sweating. The release of acetylcholine could be due to the stimulation of cholinergic post- ganglionic sympa-thetic nerve fibers to the sweat glands.[51] Adachi pos-tulated an allergy to sweat recently.[52] The skin le-sions arise within minutes after exercise, emotions or taking hot spicy foods. The lesions last for 1-2 hours. The urticaria may be associated with systemic symptoms like flushing and fainting.[53] The weals may be reproduced after excercise in a hot environment[54] Intradermal injection of methacholine produces sweating and weal formation but is not a reliable test.[54]

Cold urticaria

In this type, cold in any form like cold winds, cold temperature, cold liquids etc., precipitate urti-caria. Idiopathic cold urticaria is the most common type.[55] On exposure to cold itching and wealing of the skin occur within minutes and lasts upto 1 hour. The diagnosis may be confirmed by keeping an ice cube on the forearm for 10 minutes and reproducing the weal response. Familial cold urticaria is inherited as an autosomal dominant trait.[56] Cold urticaria oc-curs in 3% of people with cryoglobulenemia.[2] Der-mographism and cholinergic urticaria may be asso-ciated with idiopathic cold urticaria. The average duration of this condition was 6 years in one series.- The antigen responsible to produce cold urticaria may be a protein produced normally by cold exposure. Histamine is an important mediator although PGD2 may also be responsible.

Solar urticaria

This is a rare disorder in which the weals are produced by various spectrum of sunlight.[58] It may occur as a primary or sometimes secondary to topi-cal tar preparations or oral agents like chlorprom-azine.[59] The skin lesions are confined to the exposed areas. There is a sharp demarcation at the margins of clothing. Lesions slowly disappear within a few hours.[59] The skin lesions may be reproduced by exposure to artificial light sources. Solar urticaria occurs as an allergic Type I hypersensitivity response to cutaneous or circulating photo-induced antigen.[60] Protective clothing and avoidance of sunlight seem to be beneficial to these patients. Secondary solar urticaria improves if triggering factors are avoided.

Aquagenic urticaria

This is caused by contact with water which carries an epidermal antigen to the senstitized mast cells.[61] Contact urticaria[2] occurs due to direct con-tact allergens like foods, food additives, drugs, ani-mal dander, caterpillar, grass pollen, algae etc. Hair dressers may develop contact urticaria to ammonium persulfate.

Angio-oedema

This is a variant of urticaria where there is involvement of the subcutaneous tissue.[62] The skin lesions may appear on the eyelids, lips, genitalia, tongue and pharynx. Sudden onset appears to be characteristic. The skin lesions last for few hours to few days.[5] Angio-oedema may present as an emer-gency in dermatology and needs to be treated ag-gressively. Heriditary angio-oedema is a rare disor-der transmitted as an autosomal dominant trait on chromosome.[11] It starts in childhood as recurrent swellings on the skin and mucus membrane and per-sists throughout life.[63] The skin lesions are non itchy. The lesions may precede a trauma or appear spontaneously. The condition occurs due to deficiency of C1 esterase inhibitor.[64] The cause of death has been attributed to respiratory obstruction. Angio-tensin converting enzyme inhibitors (ACEI) can also produce angio-oedema.[65] Acquired C1 esterase in-hibitor deficiency may occur rarely in B-cell lymphoma or systemic lupus erythematosus.[2] Muckle and Wells, in 1961 described the combination of urticaria, deaf-ness and amyloidosis[66] which is named after them. This syndrome is inherited as autosomal dominant.

Management

Understanding the various possible causes is the first step in assessing urticaria. Allergic and drug-induced urticaria respond to removal of cause.[67] The weal is due to localized increase in capillary and venu-lar permeability caused predominantly by histamine but other mediators are also involved. The flare is due to stimulation of axon reflex mediated by neuro peptides. Pruritus results from activation of free nerve endings in the skin by histamine and other media-tors.[15] Hence histamine is the main mediator of urti-caria.[2],[15] Traditional classic antihistamines exhibit se-dation, anti cholnergic properties and paradoxical ex-citation in children as side effects.[2] An ideal antihis-tamine should have a quick onset of action and less side effects besides convenient dosage schedule. The new generation antihistamines fulfill these criteria and are the main stay of treatment especially in chronic idiopathic urticaria.[68],[69]

Terfenadine is as effective as chlorph-eniramine[70] and hydroxyzine but less sedative. Mac-rolide antibiotics, antifungals and cyclosporin are avoided with terfenadine as these drugs might com-plete with it for metabolism.[69] Cardiac arrhythmias may result if given in excess dosage i.e. more than 120 mg/day for an adult.[71]

Astemizole is very useful in chronic idiopathic urticaria and also in angio-oedema;[72] and dermog-raphism. The dose is 10 mg/day. A dose of 20 mg/ day may cause ventricular arrhythmias.[73]

Loratadine is intermediate between fast act-ing terfenadine and slower astemizole but less ef-fective than cetirizine.[74] The dose is 10 mg/day. Freidman reviewed 2500 patients on loratadine and found that the side effects are very minimal.[75]

Cetirizine is compared more favourably with other non sedating anti-histamines.[76] Dose of 10 mg/day had a more rapid and long lasting effect when compared to terfenadine or loratadine. In European studies, this drug showed only a slight increase in the incidence of sedation over a placebo.[77] However sedation is less than that caused by classical antihis-tamines.[69]

Fexofenadine has been used in the treatment of chronic idiopathic urticaria at a dose of 180 mg per day. Notably Q-T interval prolongation occasion-ally seen with the parent compound, terfenadine, does not occur with fexofenadine.[78],[79]

Antihistamines cross the placenta but are not teratogenic. They are better avoided in pregnancy and especially in the first trimester. Terfenadine is relatively safer in pregnancy.[2]

The ideal drug for chronic urticaria would need to have a broad spectrum of activities antagonizing not only histamine but also a range of other media-tors such as neuropeptides, and possibly PAF and IL-I as well.[68] Combination of H1 and H2 antihista-mine has a limited role in refractory urticaria and may provide additional benefit in less than 50% of these patients.[80] Cimetidine at a dose of 800 mg/ day in divided doses cleared the lesions in few patients only.[81] Satisfactory orally effective mast cell stabilizing drugs are not available. The poorly ab-sorbed sodium chromoglycate has been reported to be beneficial in an uncontrolled trial of food additive - aggravated urticaria.[82] Drugs that have combined properties of H1 antihistamine and a mast cell stabi-lizer, such as ketotifen and oxatomide, are no more effective than antihistamines.[68] On the contrary good therapeutic results have been obtained by Pinol.[83] When the conventional H1 and H2 antihistamine failed, other drugs like nifidipine is used as an ad-junct to antihistamines.[84] Similarly in a limited num-ber of patients, low-dose cyclosporin - A, treated was found to be effective.[85] In resistant cases a brief course of systemic corticosteroid therapy may be nec-essary but the extended use of systemic corticoster-oids should be avoided because of significant ad-verse effects.[86],[87] As urticaria patients have signifi-cant psychological problems it is suggested that ad-junctive treatment of urticaria should focus primarily on stress management training aimed at relieving anxiety and group therapy which focuses on an ex-ploration of interpersonal issues.[88] Doxepin hydro-chloride, a tricyclic antidepressant significantly sup-pressed histamine and codeine induced cutaneous weal response.[89] Non specific immunotherapy such as plasmapheresis and intravenous immunoglobulin are effective in some.[6],[90] In an open trial topical ste-roids also have been found to be effective.[91] Adrenalin is used in the emergency treatment of nonheredi-tary angioedema involving larynx. It can be injected intramuscularly, subcutaneously or inhaled depend-ing upon the severity of the reaction.[2] UVB or PUVA therapy may improve dermographism.[92] Cold urti-caria can be managed by repeated exposure to cold and inducing tolerance apart from H1 antagonists.[93] Solar urticaria may be minimized by wearing appro-priate clothing, avoidance of sunlight, or applying broad spectrum sun screens. Plasmapheresis is also useful in some.[94]

1.	Warin RP, Champion RH. Urticaria. London: WB Saunders, 1974. [Google Scholar]
2.	Kobza Black A, Champion RH. Urticaria. In: Textbook of Dermatology, Champion RH, Burton JL, Burns DA & Breathnac SM eds. Sixth edition, Blackwell Science, 1998; 2113-2139. [Google Scholar]
3.	Champion RH, Greaves MW, Kobza Black A, Pye RJ eds. The Urticarias. Edinburg: Churchill Livingstone, 1985. [Google Scholar]
4.	Rook AJ, Maibach HI, Jublin L. (eds). Urticaria. Seminars in Dermatology, Vol 6. Philadelphia: Grune & Stratton, 1987; 272 - 356. [Google Scholar]
5.	Champion RH, Roberts SOB, Carpenter RG, et al. Urticaria and angio-oedema: a review of 554 patients. Br J Dermatol 1969 ; 81: 588 -597. [Google Scholar]
6.	Greaves MW, O' Donnel BE Not all chronic urticaria is "idiopathic". Exp Dermatol 1998 ; 7: 11-13. [Google Scholar]
7.	Buhner D, Grant JA. Serum sickness. Dermatol Clin 1985; 3: 107 - 117. [Google Scholar]
8.	Illing L. Physical urticaria, its diagnosis and treatment. In: Mali JWH ed. Current Problems in Dermatology, Vol 5. Basel: Karger, 1973:79 -116. [Google Scholar]
9.	Kobza Black A. The physical urticarias. In: Champion RH, Greaves MW, Kobza Black A, et al, eds. The Urticarias. Edinburg: Churchill Livingstone, 1985: 168 -190. [Google Scholar]
10.	Hide M, Francis DM, Grattan CEH, et al. The pathogenesis of chronic idiopathic urticaria: new evidence suggests an auto immune basis and implications for treatment. Clin Exp Allergy 1994; 24 ; 624-627. [Google Scholar]
11.	Niimi N, Francis DM, Kermani F, et al. Dermal mast cell activation by auto-antibodies against the high affinity IgE receptor in chronic urticaria. J Invest Dermatol 1996; 106: 1001-1006. [Google Scholar]
12.	Grattan CEH, Francis DM, Slater NCP, et al. Plasmapheresis for severe chronic urticaria. Lancet 1992; 339: 1078-1080. [Google Scholar]
13.	O' Donnell BF, Barlow RI, Kobza Black, et al. Response of severe chronic urticaria to intravenous immunoglobulin. Br J Dermatol 1994; 131 (Suppl.44): 23-4A. [Google Scholar]
14.	Kobza Black A, Greaves MW, Champion RH, et al. The urticarias 1990. Br 3 Dermatol 1991; 124: 100-108. [Google Scholar]
15.	Kobza Black A, Grattan CEH. The mediators involved in acute and chronic urticaria and their therapeutic implications. In: Champion RH, Pye RJ eds. Recent Advances in Dermatology Vol 9. Edinburg: Churchil Livingstone, 1992; 119 - 133. [Google Scholar]
16.	Martini A, Ravelli A, Albani S, et al. Hypocomplementaemic urticarial vasculitis syndrome with severe systemic manifestations. J Pediatrics 1994; 124: 742-744. [Google Scholar]
17.	Wisnieski JJ, Emancipator SN, Korman NJ, et al. Hypocomplementaemic urticarial vasculitis syndrome in identical twins. Arth Rheumat 1994; 37: 1105 - 1111. [Google Scholar]
18.	Jordan HF, Schneider JW. Papular urticaria: a histopathologic study of 30 patients. Am I Dermatopathol 1997; 19: 119-126. [Google Scholar]
19.	Scheldon IM, Mathews KP, Lovell RG. The vexing urticaria problem. Present concepts of etiology and management. J Allergy 1954; 25: 525-560. [Google Scholar]
20.	Hellgren L. The prevalence of urticaria in the total population. Acta Allergol 1972 ; 27: 236 - 240. [Google Scholar]
21.	Champion RH. Acute and chronic urticaria. Semin Dermatol 1987; 6: 286 -291. [Google Scholar]
22.	ZuberbierT, Ifflander J, Semmler C, et al. Acute urticaria: Clinical aspects and therapeutic responsiveness. Arch Dermatol 1996;76: 295 - 297. [Google Scholar]
23.	Aoki T, Kojima M, Horiko T Acute urticaria: History and natural course of 50 cases. J Dermatol 1994; 21: 73-77. [Google Scholar]
24.	Stevenson DD. Diagnosis, prevention and treatment of adverse reactions to aspirin and non steroidal anti inflammatory drugs. I Allergy Clin Immunol 1984; 74: 617. [Google Scholar]
25.	Ormerod AD, Reid TMS, Main RA. Penicillin in milk - its importance in urticaria. Clin Allergy 1987; 17: 229-234. [Google Scholar]
26.	Cowdrey SC, Reynolds IS. Acute urticaria in infectious mononucleosis. Ann Allergy 1969; 27: 182-187. [Google Scholar]
27.	Sibbald RG, Cheema AS, Lozinski A, et al. Chronic urticaria. Evaluation of the role of physical, immunologic, and other contributory factors. Int J Dermatol 1991; 30: 381-386. [Google Scholar]
28.	Tebbe B, Geilen CC, Schulzke JD, et al. Helicobacter pylori infection in chronic urticaria. J Am Acad Dermatol 1996; 34: 685-686. [Google Scholar]
29.	Gosh S, Kanwar AJ, Dhar S, et al. Role of gastrointestinal parasites in urticaria. Indian I Dermatol Venereol Leprol 1993; 59: 117-119. [Google Scholar]
30.	Numata T, Yanomota S, Yamura T. The role of mite allergen in chronic urticaria. Ann Allergy 1979; 43: 356-358. [Google Scholar]
31.	Young E, Stoneham MD, Petruckevitch A, et al. A population study of food intolerence. Lancet 1994; 343: 1127-1130. [Google Scholar]
32.	Reisman RE. Insect stings. N Engl J Med 1994; 331: 523-527. [Google Scholar]
33.	Collet E, Petit JM, et al. Chronic urticaria and thyroid autoimmunity. Ann Dermatol Venereol 1995; 122: 413-416. [Google Scholar]
34.	Rumbyri IS, Katz JL, Schoket AL. Resolution of chronic urticaria in patients with thyroid autoimmunity. I Allergy Clin Immunol 1996; 96: 901-905. [Google Scholar]
35.	Koblenzer C. Psychosomatic concepts in Dermatology. A dermatologists-psycho analyst's view point. Arch Dermatol 1983; 119:501-512. [Google Scholar]
36.	Gupta MA, Gupta AK, Schork NJ, et al. Depression modulates pruritus perception: a study of pruritus in psoriasis, atopic dermatitis and chronic idiopathic urticaria. Psychosom Med 1994; 56: 3640. [Google Scholar]
37.	Kztz HI Anaphylactic syndromes. In: Dermatology, Moschella SL, Hurely HJ eds. 2nd edn Philadelphia: WB Saunders Company 1985: 264 -266. [Google Scholar]
38.	Mehregan DR, Hall MJ, Gibson LE. Urticarial vasculitis: a histopathologic and clinical review of 72 cases. J Am Acad Dermatol 1992; 26:441-448. [Google Scholar]
39.	Russel Jones R, Bhogal B, Dash A, et al. Urticaria and vasculitis: a continuum of histological and immunopathological changes. Br I Dermatol 1983 ; 108: 695 - 703. [Google Scholar]
40.	Champion RH. Urticaria then and now. Br I Dermatol 1988; 119: 588 - 597. [Google Scholar]
41.	Lewis T Vascular reactions of the skin to injury -1. Reactions to stroking. Urticaria factitia. Heart 1924 ; 2: 119 - 129. [Google Scholar]
42.	Breathnach SM, Allen R, Milford Ward A, et al. Symptomatic dermographism: natural history, clinical features, laboratory investigations and response to therapy. Clin Exp Dermatol 1983; 8: 463 -476. [Google Scholar]
43.	Wong RC, Fairley JA, Ellis CN. Dermographism; a review. J Am Acad Dermatol 1984; 11: 643 - 652. [Google Scholar]
44.	Smith JA, Mansfeld LE, Fokakis A, et al. Dermographia caused by IgE mediated penicillin allergy. Ann Allergy 1983 ; 51: 30 - 330. [Google Scholar]
45.	Mayou SC, Kobza Black A, Greaves MW. Cholinergic dermographism. Br J Dermatol 1986 ; 115: 371 - 377. [Google Scholar]
46.	Warin RR Factitious urticaria and red dermographism. Br I Dermatol 1981; 104: 285 - 288. [Google Scholar]
47.	Warin RP. Clinical observations on delayed pressure urticaria. Br 3 Dermatol 1989 ; 121: 225-228. [Google Scholar]
48.	Dover IS, Kobza A, Milford Ward A. Delayed pressure urticaria: clinical features, laboratory investigations and response to therapy of 44 patients. I Am Acad Dermatol 1988; 18: 1289-1298. [Google Scholar]
49.	Barlow RJ, Ross EL, Mac Donald D, et al.Adhesion molecule expression and the inflammatory cell infiltrate in delayed pressure urticaria. Br J Dermatol 1994; 131: 341-347. [Google Scholar]
50.	Ryan TI, Shim - Young N, Turk JL. Delayed pressure urticaria. Br I Dermatol 1968 ; 80: 485 - 490. [Google Scholar]
51.	Grant RT, Bruce Pearson RS, Comeau WJ. Observation on urticaria provoked by emotion, by exercise and by warming the body. Clin Sci 1936 ; 2: 253 - 272. [Google Scholar]
52.	Adachi J, Aoki T, Yamatodani A. Demonstration of sweat allergy in cholinergic urticaria. J Dermatol Sci 1994; 142: 142 - 149. [Google Scholar]
53.	Czarnetzkin BM, galinski C, Meister R. Cutaneous and pulmonary reactivity in cholinergic urticaria. Br J Dermatol 1984; 110 887-910. [Google Scholar]
54.	Commens CA, Greaves MW. Tests to establish the diagnosis of cholinergic urticaria. Br I Dermatol 1978 ; 98: 47 - 51. [Google Scholar]
55.	Nettaonmaki H. Cold urticaria. Clinical findings in 220 patients. J Am Acad Dermatol 1985; 13: 636 - 644. [Google Scholar]
56.	Doeglas HM, Bleumink E. Familial cold urticaria. Clinical findings. Arch Dermatol 1974 ; 110: 382 - 388. [Google Scholar]
57.	Heavey DJ, Kobza Black A, Barrow SE, et al. Prostaglandin D2 and histamine release in cold urticaria. J Allergy Clin Immunol 1986; 78: 458 - 461. [Google Scholar]
58.	Horio T, Fujigaki K. Augmentation spectrum in solar urticaria. J Am Acad Dermatol 1988; 18: 1189 -1193. [Google Scholar]
59.	Magnus IA. Solar urticaria. In: Dermatological Photobiology. Oxford: Black well Scientific Publications. 1986 ; 202 - 210. [Google Scholar]
60.	Leenutaphong V, Holzle E, Plewig G. Pathogenesis and classification of solar urticaria: a new concept. J Am Acad Dermatol 1989 21: 237 - 240. [Google Scholar]
61.	Czarnetzki BM, Breetholt KH, Traupe H. Evidence that water acts as a carrier for an epidermal antigen in aquagenic urticaria. J Am Acad Dermatol 1986 ; 15: 623 - 627. [Google Scholar]
62.	Greaves MW, Lawlor F. Angio - oedema: manifestations and management. J Am Acad Dermatol 1991; 25: 155 -161. [Google Scholar]
63.	Colten HR. Heriditary angioneurotic edema 1887 -1987. N Engl J Med 1987 ; 317: 43 - 44. [Google Scholar]
64.	Donaldson VH, Evans RR. A biochemical abnormality in heriditary angioneurotic oedema. Am J Med 1963 ; 35: 37 - 44. [Google Scholar]
65.	Sabroe RA, Kobza Black A. Angiotensin converting enzyme inhibitors and angio-oedema. Br J Dermatol 1997 ; 136: 153 -158. [Google Scholar]
66.	Muckle TJ, Wells MV. Urticaria, deafness and amyloidosis: a new heredo familial syndrome. Q J Med 1961 ; 32: 235 - 248. [Google Scholar]
67.	Ormerod AD. Urticaria, recognition, causes and treatment. Drugs 1994; 48: 717 - 730. [Google Scholar]
68.	Simons FER, Simons KJ. The pharmacology and the use of H1receptor antagonist drugs. N Engl J Med 1994 ; 330: 1663 - 1670. [Google Scholar]
69.	Valia RG. New antihistamines - Review. What's New Dermatology, Sexually Transmitted Diseases and Leprosy 1997 ; 10: 1-9. [Google Scholar]
70.	Grand JA, Bernstein DJ, Buckley CE, et al. Double blind comparison of terfenadine, chlorpheniramine and placebo in the treatment of idiopathic chronic urticaria. J Allergy Clin Immunol 1988; 81: 574 - 579. [Google Scholar]
71.	Boggs PB, Ellis CN, Grossman J, et al. Double -blind placebo controlled study of terfenadine and hydroxyzine in patients with chronic idiopathic urticaria. Ann Allergy 1989; 63: 616 - 620. [Google Scholar]
72.	Kailasam V, Mathews KR Controlled clinical assessment of astemizole in the treatment of chronic urticaria. Pharmacotherapeutics 1986; 4 ; 679-686. [Google Scholar]
73.	Craft t. Torsade due points after astemizole overdose Br Med J.5 1986; 292: 660. [Google Scholar]
74.	Pechadre JC, Beudin P, Eschalier A, et al. A comparison of central and peripheral effects of cetrizine and loratidine. J Int Med Res 1991; 19: 289 -295. [Google Scholar]
75.	Friedman HM. Loratadine: A potent non sedating longstanding H1 antagonist. Am J Rhinol. 1987; 1: 95 - 99. [Google Scholar]
76.	Kalivas J, Breneman D, Tharp M, et al. Urticaria: Clinical efficacy of cetirizine in comparison with hydroxyzine and placebo. J Allergy Clin Immunol 1990 ; 86: 1014 - 1018. [Google Scholar]
77.	Kennard CB, Ellis CN. Pharmacologic therapy of urticaria. J Am Acad Dermatol 1991; 25: 176 - 187. [Google Scholar]
78.	Simpson K, Jarvis B. Fexofenadine: a review of its use in the management of seasonal allergic rhinitis and chronic idiopathic urticaria. Drugs 200; 59: 301-321. [Google Scholar]
79.	Paul E, Berth-Jones J, Ortonne JP, et al. Fexofenadine hydrochloride in the treatment of chronic idiopathic urticaria: a placebo controlled, parallel group, dose-ranging study. J Dermatol Treat 1998; 9: 143 - 149. [Google Scholar]
80.	Manroe EW. Cohen SM, Kalbfeisch J, et al. Combined H1 and H2 therapy in chronic urticaria. Arch Dermatol 1981; 117: 404 - 407. [Google Scholar]
81.	Sing G. H2 blockers in chronic urticaria. Int J Dermatol 1984; 23: 627 - 628. [Google Scholar]
82.	August R Successful treatment of urticaria due to food additives with sodium cromoglycate and an exclusion diet. In: The Mast Cell: Its Role in Health and Disease. Pepys J, Edwards Am eds. London: Pitmen Medical, 1979: 584 -90. [Google Scholar]
83.	Pino J, Carapeto FJ. Ketotifen in the treatment of chronic urticaria and angioneurotic oedema. Allergol Immunopathol 1984; 12:19-27. [Google Scholar]
84.	Bressler RB, Sowell K, Huston DR Therapy of chronic idiopathic urticaria with nifidipine: demonstration of beneficial effect in a double blinded, placebo-controlled, cross over trial. J Allergy Clin Immunol 1989; 83: 756-763. [Google Scholar]
85.	Toubi E, Blant A, et al. Low dose cyclosporin A in the treatment of severe chronic idiopathic urticaria. Allergy 1997;52:312-316. [Google Scholar]
86.	Thrap MD. Chronic urticaria: pathophysiology and treatment approaches. J Allergy Clin Immunol 1996; 98: 325-330. [Google Scholar]
87.	Paradis L, Lavoie A, Burnet C, et al. Effects of systemic corticosteroids on cutaneous histamine secretion and histamine releasing factor in patients with chronic idiopathic urticaria. Clin Exp Allergy 1996; 26: 815-820. [Google Scholar]
88.	Spreber J, Shaw J, Bruce S. Psychological components and the role of adjunct interventions in chronic idiopathic urticaria. Psychother Phychosom 1989; 51: 135-141. [Google Scholar]
89.	Gold sobel AB, Rohr AS, Siegel SC, et al. Efficacy of doxepin in the treatment of chronic idiopathic urticaria. J Allergy Clin Immunol 1986; 78: 867 - 873. [Google Scholar]
90.	Sabroe RA, Greaves MW. The pathogenesis of chronic idiopathic urticaria. Arch Dermatol 1997; 133: 1003-1008. [Google Scholar]
91.	Ellingsen AR, Thestrup P. Treatment of chronic idiopathic urticaria with topical steroids. An open trial. Acta Derm Venereol 1996; 76: 43-44. [Google Scholar]
92.	Logan RA, O'Brien TJ, Greaves MW. The effect of psoralen photochemotherapy (PUVA) on symptomatic dermographis j. Br J Dermatol 1989 ; 14: 25-28. [Google Scholar]
93.	Bentley - Philips CB, Kobza Black A, Greaves MW. Induced tolerance in cold urticaria caused by cold evoked histamine release. Lancet 1976; ii: 63-66. [Google Scholar]
94.	Duscht P, Leyen P, Schwarz T, et al. Solar urticaria: effective treatment by plasmapharesis. Clin Exp Dermatol 1987 ; 12: 185-188. [Google Scholar]