Year : 2006 | Volume
: 51 | Issue : 3 | Page : 171--177
Chronic urticaria: An overview
Sudha Yadav, Amitabh Upadhyay, AK Bajaj
From Bajaj Skin Clinic, Allahabad, India
A K Bajaj
3/6, Pannalal Road, Allahabad - 211002
Urticaria is a fairly common condition characterized by transient swellings of the skin. This could be an extremely disabling and difficult-to-treat condition. Chronic urticaria has multifactorial aetiologies including intolerance to food or drugs, infectious diseases, and autoimmune processes. With the demonstration of auto antibodies against IgE receptor or IgE itself, a new subset of chronic urticaria has been identified as autoimmune urticaria. Further studies in this field in the recent past have contributed considerably in understanding the pathomechanism of urticarias in a better way. Controlled trials with immunomodulator drugs have further broadened our pharmacologic approach, especially in patients with severe refractory urticaria. This article reviews the types of urticaria, its causes, pathophysiologic basis and current approaches in its management.
|How to cite this article:|
Yadav S, Upadhyay A, Bajaj A K. Chronic urticaria: An overview.Indian J Dermatol 2006;51:171-177
|How to cite this URL:|
Yadav S, Upadhyay A, Bajaj A K. Chronic urticaria: An overview. Indian J Dermatol [serial online] 2006 [cited 2021 Oct 18 ];51:171-177
Available from: https://www.e-ijd.org/text.asp?2006/51/3/171/27978
Chronic urticaria is associated with diverse clinical presentations and causes. Conventionally it is defined as the repeated occurrence of daily or almost daily cutaneous wheals accompanied by redness and itching for more than 6 weeks. Superficial swellings of the dermis are called wheals, whereas, the deeper swellings of the dermis and subcutaneous and/or sub mucosal tissues are called angioedema. Most episodes of acute urticaria last for only a short duration, but chronic urticaria can be quite distressing and even disabling for many patients. Symptomatically urticaria looks like an allergic reaction, yet often the disease process is autoimmune or idiopathic in nature.
The term chronic urticaria makes no assumption about its cause. In a number of patients it is associated with various aggravating factors including drugs, food and food additives, infections and infestations, systemic diseases etc. Circulating antibodies against the high affinity IgE receptors and anti FCeRIa antibodies have been detected on mast cells in about 30 to 50% cases of chronic urticaria. In spite of extensive laboratory investigations,50% cases of chronic urticaria remain idiopathic.
Approximately 15 to 20% of the general population will have urticaria at least once during their lifetime. Although persons of any age may experience urticaria and/or angioedema, the urticaria occurs most frequently after adolescence, with the highest incidence in young adults. The exact incidence and prevalence of chronic urticaria are not known, although it occurs in at least 0.1% and possibly up to 3% of the population. Chronic urticaria is twice as common in women as in men. An Indian study showed that out of 500 cases of urticaria, 37% were suffering from physical urticaria.
There are reports that HLA-DRB1*4,HLA-DQB1*0302,HLA-DOB1*06 have been found with increased frequency in patients with chronic idiopathic urticaria as compared with a control population. HLA-DRB1*4, HLA-DQB1*0301/4, HLA-DQB1*0302 have been found in increased frequency in patients with anti-FCeRIa auto antibodies.
Both urticaria and angioedema, are associated with dilation of the venules. Urticaria and/or angioedema are characterized by shorts lived swellings of the skin and mucous membranes due to transient leakage of plasma from small blood vessels into the surrounding connective tissue. Oedema involving the superficial portion of the dermis is characteristic of urticaria, whereas, angioedema involves the deeper dermis and subcutaneous tissue. Superficial swelling of the dermis is known as wheal and the surrounding flare is due to an axon reflex. Histopathological findings of urticarial wheals are usually nonspecific, comprising of vascular and lymphatic dilatation, edema and a variable perivascular cellular dermal infiltrate. The spectrum of cellular changes depends upon the age of the wheals and their underlying cause. In acute urticaria, there is interstitial dermal oedema, dilated venules with endothelial swellings and a few inflammatory cells, whereas in chronic urticaria besides the dermal edema, a perivascular and interstitial cellular dermal infiltrate consisting of lymphocytes, monocytes, neutrophils and eosinophils is also seen. In the majority of wheals, there is a sparse perivascular infiltrate, predominantly of helper-T lymphocytes.
Urticaria was named after the stinging nettle plant (Latin, urtica), which is now known to contain histamine. The importance of histamine as a mediator of urticaria has been recognized for many years. The mast cell is believed to be the major effecter cell in most forms of urticaria, though other cell types may be involved. Degranulation of mast cells with release of histamine is central to the development of wheals and angioedema. Urticaria is due to a local increase in permeability of capillaries and venules. These changes are dependent on activation of the cutaneous mast cells, which contain a range of mediators predominantly histamine. Vascular permeability in skin is produced by the interaction of both H 1 and H 2 histamine receptors. Activation of H 1 receptors in the skin induces itching, flare, erythema, whealing and contraction of smooth muscle in respiratory and gastro-intestinal tract. Activation of H 2 receptors contributes to erythema and whealing in the skin and increased gastric acid secretion. Histopathologically chronic urticaria is characterized by an inflammatory infiltrate comprising of CD4 + and CD8 + T lymphocytes, eosinophils, basophils and neutrophils. With the discovery of IgG anti-IgE antibodies and the more common IgG anti-FCeRIa antibodies in the sera of some patients with chronic urticaria, the term 'autoimmune urticaria' is commonly used for these patients.
Traditionally urticaria is classified in to acute and chronic, with a time division arbitrarily chosen at 6 weeks to 3 months. When the tendency to wheals format is present for less than 6 weeks, urticaria is termed acute, whereas if wheals continue on most days for longer than 6 weeks, it is categorized as chronic. If the episodes are of shorter duration than the symptom free period, the urticaria is considered recurrent. A working classification [Table 1] distinguishes urticaria provoked by physical stimuli, skin contact, or small vessel vasculitis from other presentations, which are grouped under the term 'ordinary urticaria'.
Urticaria clinically presents as circumscribed, raised (edematous), usually pruritic evanescent skin lesions. The lesions may be pink or red, although classically they are pale wheals surrounded by an erythematous flare. The individual lesions of urticaria arise suddenly, rarely persist for more than 24 hours, and may continue to recur for an indefinite period. These lesions usually are discrete, round or oval in shape; less commonly they may be irregular, serpiginous, or gyrate. Urticarial wheals are variable in size ranging from a few millimeters to lesions involving whole extremity. Lesions may appear anywhere on the body including scalp, palms and soles. In 50% of cases urticaria is associated with angioedema. Wheals usually resolve within 24 hours passing through a macular erythematous phase, but nearly always leaving the skin with a normal appearance. Urticarial wheals are very itchy and patients tend to rub rather than scratch, hence excoriation marks are not seen. Headache, dizziness, hoarseness, wheezing, sensation of a lump in the throat, shortness of breath, nausea, vomiting and an abdominal pain, diarrhea and arthralgias may occur as concomitant systemic manifestations of severe episodes of urticaria.
Depending upon the various aggravating factors and the presence of circulating auto antibodies, chronic urticaria can be further divided in three subgroups:
Chronic urticaria with potential provoking factorsAutoimmune urticariaChronic idiopathic urticaria (CIU)
Chronic urticaria with potential provoking factors
These include drugs, food, food additives, infections (bacterial, viral, fungal), parasitic infestations, collagen and endocrine disorders, dermatological disorders etc.
Drugs : Drugs frequently cause acute urticaria, but these are also associated with chronic urticaria. Aspirin may exacerbate chronic urticaria in 6.7 to 67% of patients.,, The causal relationship between penicillin and chronic urticaria is a complex one. Though ACEIs (angiotensin converting enzyme inhibitors) are commonly associated with angioedema they rarely cause chronic urticaria also. Other drugs implicated are alcohol, narcotics (codeine, morphine) and oral contraceptives. Food and food additives : The reported incidence of chronic urticaria exacerbated by specific food varies from 2 to 30% or more, but an allergic cause for all ordinary urticarias has been found in fewer than 3.5%. More frequently implicated food additives are tartrazine, other azo dyes including amaranth and sunset yellow, benzoic acid compounds etc. Infections/infestations : Chronic urticaria is frequently flared by intercurrent viral infections. The incidence of bacterial infections such as dental sepsis, sinusitis, gall bladder, and urinary tract infection varies in different series.,, A possible role of Helicobacter pylori has also been suggested in chronic urticaria. Fungal infections such as onychomycosis, tinea pedis and candida have been considered as possible associations. Chronic urticaria has been associated with parasitic infestations such as strogyloidiasis, giardiasis and amoebiasis, particularly in developing and underdeveloped countries. Systemic diseases : Among the systemic causes the most significant conditions belong to the categories of rheumatic, other autoimmune disorders including thyroiditis, and neoplasm. Though collagen vascular diseases usually cause urticarial vasculitis rarely do they cause chronic urticaria also. Chronic urticaria can be seen as a manifestation of hypothyroidism (Hashimoto's thyroiditis) or hyperthyroidism (Graves' disease), but patients most commonly are clinically and biochemically euthyroid., Miscellaneous: Grass pollens, mould, spores, animal dander, house dust and even tobacco smoke may provoke chronic urticaria. Urticaria may worsen during pregnancy and also premenstrually. Urticaria has been associated with a metal pin in femur, metal dental prostheses, and with dental amalgams.,, Depression may also cause or aggravate chronic urticaria. Many dermatological conditions such as urticaria pigmentosa, dermatitis herpetiformis, pemphigoid etc may also produce urticaria-like lesions.
In 1983, Leznoff et al suggested an autoimmune basis for the urticaria. This was after the observation that there was an association between thyroid disease and chronic idiopathic urticaria. After that in 1988 Gruber et al detected functional anti IgE antibodies and proposed that these could be the cause of urticarial wheals. In 1991 Grattan et al showed evidence of histamine releasing auto antibodies with anti-IgE properties in sera from chronic idiopathic urticaria patients. Since 1993 it is well established that about 30 to 50% patients with chronic urticaria have circulating functional auto antibodies against the high affinity IgE receptor (FCeRIa) or against IgE. These auto antibodies appear to be specific to the patients with chronic urticaria.
Mast cells and basophils express FCeRIa. This receptor consists of 4 transmembrane polypeptide chains, i.e., 1a, 1β , and 2c chains. The second domain of the extra cellular part of the a-chain binds with the central domain Ca3 of the Fc region of IgE. Mast cells and basophils are activated by cross linkage of FCeRIa receptors, usually via surface bound antigen specific IgE. This cross linkage of FCeRIa receptor is only one of the several triggers for degranulation. The anti FCeRIa auto antibodies, which are of isotypes IgG1 or IgG3, release histamine from mast cells and basophils and are therefore functional. Nonfunctional anti-FCeRIa auto antibodies have been detected in the sera of patients with autoimmune disease such as dermatomyositis and pemphigus vulgaris and some healthy subjects. These auto antibodies do not release histamine from basophils and are predominantly of subtypes IgG2 and IgG4.
Points in favour of the autoimmune hypothesis of the chronic urticaria include reproducibility of the autologous serum skin test through passive transfer of serum of affected patients into the skin of healthy subjects; correlation of functional auto antibody plasma levels with disease severity; and disease remission following removal or suppression of the antibody. An increased incidence of a particular major histocompatibility complex class II allele (HLADR4) in patients with chronic urticaria is in agreement with the proposed autoimmune origin. Evidence for autoimmune thyroid disease and abnormal thyroid function was largely found among the autologous serum skin test (ASST) positive patients, supporting an autoimmune etiology in this subgroup of patients.
The diagnosis of autoimmune urticaria depends primarily on clinical suspicion that is supported by tests when available. Although patients with autoimmune antibodies have no distinctive diagnostic clinical features, the diagnosis of chronic urticaria often can be suspected from a history of highly symptomatic and severe continuous whealing associated with systemic features of malaise, indigestion, and feeling hot or cold. A past or family history of autoimmune diseases, especially thyroiditis, can give a clue. Histological examination in these cases shows pronounced eosinophil degranulation in older lesions compared with non-autoimmune cases. The in vivo test for autoimmune urticaria is autologous serum skin test, whereby the patient's own serum is centrifuged and used for skin prick testing. The gold standard in vitro methods are basophil histamine release assays, or western blot analysis, but these are not available to the majority. Peripheral blood basophil count is almost unmeasurable in autoimmune urticaria patients compared with non autoimmune, and this could be developed as a method of detection.
Chronic Idiopathic Urticaria
Even after evaluation for evidence of autoimmunity and other provoking factors, approximately 50% cases of chronic urticaria remain unexplained and are categorized as CIU. In most series, this subgroup represents a substantial number of patients, but must remain a diagnosis of exclusion.
Establishing the cause of chronic urticaria is difficult and at times almost impossible. The most important part in the investigation of urticaria is detailed and comprehensive history and thorough physical examination. The history itself can be regarded as the most valuable diagnostic tool in identifying causes of chronic urticaria. History should include information regarding time of onset, duration and distribution of individual lesions, food and food additives, home and/or work environment, enquiry about potential source of infection, accompanying systemic features e.g., fever, joint pains etc, family history of thyroid or other autoimmune diseases, history of atopy, drug intake and dental diseases.
Routine laboratory screening does not contribute substantially to the diagnosis of chronic urticaria or to the detection of underlying disorders. In chronic urticaria, only a total and differential full blood count and erythrocyte sedimentation rate (ESR) should be performed routinely. An elevated ESR suggests the possibility of an underlying systemic disease and eosinophilia would prompt a search for parasitic diseases. Screening test for thyroid function and antithyroid peroxidase and antithyroglobulin antibodies may be worth while.
Autologous serum skin test (ASST) should be performed in all the patients with chronic urticaria because a positive test suggests that an autoimmune mechanism underlies the disease. ASST requires minimal technical equipment and can be performed routinely in all allergy or dermatology outpatient clinics. The test is performed by injecting 0.05 to 0.1 ml of the patient's own serum intradermally into the flexor aspect of the forearm, 2 inches below the antecubital crease and saline control into the right forearm. A reading of wheal should be taken after 30 minutes. A wheal and flare of more than 1.5 mm diameter than that of the control is considered positive. The patient is advised to stop antihistamines for at least 3-4 days and doxepin and steroids for 4-6 weeks, before the test.
The ASST has a sensitivity of 70% and a specificity of 80%. A positive test is suggestive but not diagnostic of an autoimmune basis for the patient's chronic urticaria. Confirmation is needed by in vitro testing of the patient's serum for the anti-FCeRIa or the anti-IgE auto antibodies. In vitro 'the basophil histamine release assay' is currently the gold standard for detecting functional auto antibodies. However, it is available only at a few research centres and can not be performed as a routine.
A step by step approach to the management of chronic urticaria should be taken. There are a number of potential causes of urticaria, and the severity and clinical presentation can differ substantially from patient to patient. Many pharmacological and nonpharmacological interventions are available but none is universally acceptable. For these reasons, the treatment regimen should be tailored to the individual patient. The routine management of autoimmune and non autoimmune chronic urticaria is the same .
General measures include removal of any identifiable cause, explanation, information and reassurance. Advice regarding avoidance of alcohol overuse, excessive tiredness, stress, prolonged pressure on the skin, and overheated surroundings are important. Frequent tepid showers and application of 1% menthol or calamine in aqueous cream/lotion can be prescribed as cooling agents. Some cases of urticaria may be caused exclusively by the non allergic triggers e.g., aspirin, other NSAIDs and opiates. Even if analgesics are not the main cause for chronic urticaria, they can be an aggravating factor. Avoidance of aspirin and other NSAIDs should usually be recommended because these drugs aggravate chronic urticaria in about 30% of patients. Patients taking low dose aspirin for its antithrombotic properties can usually continue regular treatment. ACE inhibitors should usually be avoided in chronic urticaria because angioedema and, rarely, urticaria are recognized adverse effects.
The value of an elimination diet or oral food challenge is controversial. Avoidance of dietary pseudo allergens, including food colors, preservatives, and natural salicylates have been not found beneficial in treating chronic urticaria. There is a general agreement that dietary measures have no role in most forms of chronic urticaria unless proven by double-blind, placebo-controlled challenge.
Treatment of underlying diseases
Urticaria may be a manifestation of an underlying disease, and in these cases, treatment of the underlying condition may be warranted. The best example of a systemic condition that commonly is associated with chronic urticaria is autoimmune thyroid disease i.e., Hashimoto's thyroiditis. Treatment with thyroxin has been reported to alleviate the urticaria. Examples of other conditions are cryoglobulinemia and endocrine tumors. A few reports have suggested that Helicobacter pylori might be associated with chronic urticaria in some patients., According to one report, five patients with chronic urticaria went into complete remission with oral acyclovir therapy. Use of nasal filters in treating chronic urticaria has occasionally been found beneficial.
Pharmacotherapy: Depending upon the severity of the disease and response to various medicines, the drug therapy can be considered at various levels.
(A) First line therapy
Histamine is the main mediator of urticaria and H1 antihistamines represent the initial and mainstay treatment of all urticarias. These agents are reasonably effective for many patients. Different studies on role of antihistamines in chronic urticaria showed 44 to 91% response rate., The newer generation H1 antihistamines with less sedating and less cholinergic effects are preferred over the older generation H1 antihistamines as the initial choice of therapy. Antihistamines should be taken on regular basis, not as and when required to get consistent results. Antihistamines should be given with due regard to age, pregnancy, state of health, and individual response. The consensus is that in pregnancy chlorpheniramine is the safest antihistamine without any mutagenic effect. Certain antihistamines have been proposed as preferred for particular subtypes of chronic urticaria, such as hydroxizine for cholinergic urticaria or cyproheptadine for cold induced urticaria.
The treatment can be started with a second generation non sedating (or less sedating) antihistamines like cetirizine, loratidine, fexofenadine, astemizole, mizolastine, ebastine etc. Different types or combination should be tried for best response. If little response, then:
Add sedating antihistamine at night: such as hydroxyzine, diphenhydramine or the tricyclic antidepressant doxepinAdd an H2 antihistamineAdd mast cell stabilizer e.g., ketotifenβ -agonist terbutaline and the calcium channel antagonist nifedipine also have been combined with H1 antihistamine in small number of patients
(B) Second line therapy:
The use of systemic corticosteroids in the treatment of urticaria is a controversial issue. Short courses of systemic steroids (20-30 mg of prednisolone) can be given in resistant cases of chronic urticaria that have not responded to H1 antihistamine. The efficacy of corticosteroid therapy is high, but long term therapy can not be proposed because of known adverse effects, such as diabetes mellitus, hypertension, osteoporosis and gastrointestinal bleeding. Prolonged treatment of chronic urticaria with oral corticosteroids should usually be avoided except in disabling delayed or pressure urticaria and urticarial vasculitis, which are usually nonresponsive to antihistamines.
Leucotriene receptor antagonists, zafirlukast (20 mg twice daily) and montelukast (10 mg once daily) have been shown to have beneficial effect in treatment of chronic urticaria especially in cases which were aggravated by the NSAIDs and food additives. Zileuton, a 5-lipooxygenase inhibitor, which inhibits Leucotriene generation has been found to be effective in improving chronic urticaria.Rofecoxib, newer COX-2 inhibitor, has shown promising role in treating patients with refractory chronic idiopathic urticaria.
(C) Third line therapy
Immunotherapy could be tried in patients with severe refractory autoimmune urticaria. Cyclosporine has been shown to be effective in severe unremitting urticaria that had a poor response to conventional treatment with antihistamines. Long term treatment with cyclosporine over the short term therapy has not been found to be associated with more benefit in the clinical improvement.High dose of intravenous immunoglobulin has been found to be associated with some apparent benefits in the treatment of chronic urticaria. Plasmapheresis has been used to treat some patients with autoantibody positive severe chronic urticaria.According to some reports oral tacrolimus, low dose methotrexate, hydroxychloroquine, sulfasalazine, and dapsone, which have immunomodulatory properties, are effective in the treatment of chronic urticaria.,,,.Cyclophosphamide has also shown beneficial effect in treating severe autoimmune chronic urticaria.Warfarin therapy may be considered in a subgroup of patients with ASST negative chronic urticaria and angioedema unresponsive to antihistamine.In a recent placebo controlled study autohaemotherapy has shown a beneficial role in ASST positive chronic urticaria patients. Autologous serum therapy, a modified form of autohaemotherapy, has been found to be fairly effective in cases of autoimmune urticaria (personal observation, AKB).
(D) Future directions
More selective immunotherapies are possibilities. The extracellular part of the a subunit of FCeRIa or shorter peptide sequences containing the autoantibody epitopes could be used to bind to circulating FCeRIa auto antibodies, thereby inhibiting their attachment to receptors on mast cells or basophils. Also development of new therapeutic agents that inhibit other known mast cell activators or products, should be investigated for effect on treatment of urticaria.
|1||Greaves MW. Chronic urticaria. N Engl J Med 1995;332:1762-72.|
|2||Singh M, Kaur S, Kanwar AJ. Evaluation of the causes of physical urticarias. Indian J Dermatol Venereol Leprol 1990;56:109-11.|
|3||Soter NA, Kaplan AP. Urticaria and angioedema. In : Freedberg IM, Eisen AZ, Wolff K, et al , editors. Fitzpatrick's Dermatology in General Medicine. McGraw-Hill: New York; 2003. p. 1129-39.|
|4||Sabroe RA, Poon E, Orchard GE, Lane D, Francis DM, Barr RM, et al . Cutaneous inflammatory cell infiltrate in chronic idiopathic urticaria: Comparison of patients with and without anti FCeRIa or anti-IgE autoantibodies. J Allergy Clin Immunol 1999;103:484-93.|
|5||Grattan CE, Francis DM, Hide M, Greaves MW. Detection of circulating histamine releasing autoantibodies with functional properties of anti-IgE in chronic urticaria. Clin Exp Allergy 1991;21:695-704.|
|6||Hide M, Francis DM, Grattan CE, Hakimi J, Kochan JP, Greaves MW. Autoantibodies against the high-affinity IgE receptor as a cause of histamine release in chronic urticaria. N Engl J Med 1993;328:1599-604.|
|7||Champion RH, Roberts SO, Carpenter RG, Roger JH. Urticaria and angioedema: A review of 554 patients. Br J Dermatol 1969;81:588-97.|
|8||Sibbald RG, Cheema AS, Lozinski A, Tarlo S. Chronic urticaria: Evaluation of the role of physical, immunologic, and other contributing factors. Int J Dermatol 1991;30:381-6.|
|9||Stevenson DD. Diagnosis, prevention and treatment of adverse reactions to aspirin and nonsteroidal anti-inflammatory drugs. J Allergy Clin Immunol 1984;74:617-22.|
|10||Ormerod AD, Reid TM, Main RA. Penicillin in milk: Its importance in urticaria. Clin Allergy 1987;17:229-34.|
|11||Atkins FM. Food induced urticaria. In : Metcalfe DD, Sampson HA, Simon RA, editors. Food Allergy: adverse reactions to food and food additives. Blackwell Scientific Publication: Oxford; 1991. p. 129-38.|
|12||Pasricha JS, Kanwar AJ. Survey of the causes of urticaria. Indian J Dermatol Venereol Leprol 1979;45:6-12.|
|13||Kaur S, Ghosh S, Kanwar AJ. Incidence of dental caries in chronic urticaria. Indian J Dermatol Venereol Leprol 1991;57:276-8.|
|14||Pasricha JS, Gupta R. Urticaria and urinary infection. Indian J Dermatol Venereol Leprol 1981;47:277-8.|
|15||Tebbe B, Geilen CC, Schulzke JD, Bojarski C, Radenhausen M, Orfanos CE. Helicobacter pylori infection in chronic urticaria. J Am Acad Dermatol 1996;34:685-6.|
|16||James J, Warin RP. An assessment of the role of Candida albicans and food yeast in chronic urticaria. Br J Dermatol 1971;84:227-37.|
|17||Ghosh S, Kanwar AJ, Dhar S, et al . Role of gastrointestinal parasites in urticaria. Indian J Dermatol Venereol Leprol 1993;59:117-19.|
|18||Zauli D, Grassi A, Ballardini G, Contestabile S, Zucchini S, Bianchi FB. Thyroid autoimmunity in chronic idiopathic urticaria: Implications for therapy. Am J Clin Dermatol 2002;3:525-8.|
|19||Laznoff A, Sussman GL. Syndrome of idiopathic chronic urticaria and angioedema with thyroid autoimmunity: A study of 90 patients. J Allergy Clin Immunol 1989;84:66-71.|
|20||August PJ, O'Driscoll J. Urticaria successfully treated by desensitization with grass pollen extract. Br J Dermatol 1987;120:409-10.|
|21||Wilkinson SM, Beck MH, Kingston TO. Progesterone induced urticaria: Need it to be autoimmune? Br J Dermatol 1995;133:792-4.|
|22||McKenzie AW. Urticaria after insertion of Smith-Peterson vitallium nail. Br Med J 1967;67:122-6.|
|23||Espana A, Alonso ML, Soria C, Guimaraens D, Ledo A. Chronic urticaria after implantation of two nickel containing dental prostheses in a metal allergic patient. Contact Dermatitis 1989;21:204-5.|
|24||Markow H. Urticaria following a dental silver filling. N Y State J Med 1943;43:1648-52.|
|25||Shobhana S, Srinivasan TN, Vasatha J. Depression manifesting as urticaria. Indian J Dermatol Venereol Leorol 1993;59:41-2.|
|26||Leznoff A, Josse RG, Denburg J, Dolovich J. Association of chronic urticaria and angioedema with thyroid autoimmunity. Arch Dermatol 1983;119:636-40.|
|27||Gruber BL, Baeza ML, Marchese MJ, Agnello V, Kaplan AP. Prevalence and functional role of anti-IgE auto antibodies in urticarial syndromes. J Invest Dermatol 1988;90:213-7.|
|28||Grattan CE, Francis DM, Hide M, Greaves MW. Detection of circulating histamine releasing auto antibodies with functional properties of anti IgE in chronic urticaria. Clin Exp Allergy 1991;21:695-704.|
|29||Fieberger E, Hammerschmid F, Stingi G, Maurer D. Anti FCeRIa auto antibodies in autoimmune disorders. Identification of a structure function relationship. J Clin Invest 1998;101:243-51.|
|30||O'Donnell BF, O'Neill CM, Francis DM, Niimi N, Barr RM, Barlow RJ, et al . Human leucocyte antigen class II association in chronic idiopathic urticaria. Br J Dermatol 1999;140:853-8.|
|31||O'Donnell BF, Francis DM, Swana GT, Seed PT, Kobza Black A, Greaves MW. Thyroid autoimmunity in chronic urticaria. Br J Dermatol 2005;153:331-5.|
|32||Sabroe RA, Grattan CE, Francis DM, Barr RM, Kobza Black A, Greaves MW. The autologous serum skin test: A screening test for auto antibodies in chronic idiopathic urticaria. Br J Dermatol 1999;140:446-52.|
|33||Sabroe RA, Francis DM, Barr RM, Black AK, Greaves MW. Anti-Fc (episilon) RI auto autoantibodies and basophil histamine releasability in chronic idiopathic urticaria. J Allergy Clin Immunol 1998;102:651-8.|
|34||Kozel MM, Mekkes JR, Bossuyt PM, Bos JD. The effectiveness of a history based diagnostic approach in chronic urticaria and angioedema. Arch Dermatol 1998;134:1575-80.|
|35||Grattan CE. Aspirin sensitivity and urticaria. Clin Exp Dermatol 2003;28:123-7.|
|36||Grattan CE, Sabroe RA, Greaves MW. Chronic urticaria. J Am Acad Dermatol 2002;46:645-57.|
|37||Sabroe RA, Black AK. Angiotensin-converting enzyme (ACE) inhibitors and angioedema. Br J Dermatol 1997;136:153-8.|
|38||Zuberbier T, Chantraine-Hess S, Hartmann K, Czarnetzki BM. Pseudoallergen free diet in the treatment of chronic urticaria; A prospective study. Acta Derma Venereol 1995;75:484-7.|
|39||Henymann WR. Chronic urticaria and angioedema associated with thyroid autoimmunity: Review and therapeutic implication. J Am Acad Dermatol 1999;40:229-32.|
|40||Aversano M, Caizzo P, Iorio G, Ponticiello L, Lagana B, Leccese F. Improvement of chronic idiopathic urticaria with L-thyroxine: A new TSH role in immune response? Allergy 2005;60:489-93.|
|41||Reinhold U, Bruske T, Schupp G. Paraneoplastic urticaria in a patients with ovarian carcinoma. J Am Acad Dermatol 1996;35:988-9.|
|42||Wedi B, Wangler S, Werfel T, Manns MP, Kapp A. Prevalence of Helicobacter pylori associated gastritis in chronic urticaria. Int Arch Allergy Immunol 1998;116:288-94.|
|43||Di Campi C, Gasbarrini A, Nucera E, Franceschi F, Ojetti V, Sanz Torre E, et al . Beneficial effects of Helicobacter pylori eradication on idiopathic chronic urticaria. Dig Dis Sci 1998;43:1226-9.|
|44||Shelly WB, Shelly ED. Acyclovir therapy for angioedema and chronic urticaria. Cutis 1997;59:185-8.|
|45||Pasricha JS, D'Souza P. Chronic urticaria treated with soft nasal filters. Indian J Dermatol Venereol Leprol 1995;61:380-2.|
|46||Shiekh J. Advances in the treatment of chronic urticaria. Immunol Allergy clin North Am 2004;24:317-34.|
|47||Ring J, Brockow K, Ollert M, Engst R. Antihistamines in urticaria. Clin Exp Allergy 1999;29:31-7.|
|48||Nettis E, Pannofino A, D'Aprile C, Ferrannini A, Tursi A. Clinical and aetiological aspects in urticaria and angioedema. Br J Dermatol 2003;148:501-6.|
|49||Black AK, Champion RH. Urticaria. In : Champion RH, Burton JL, Burns DA, et al , eds. Textbook of Dermatology, 6th ed. Oxford, England: Blackwell Science, 1998:2113-39.|
|50||Dibbern DA Jr, Dreskin SC. Urticaria and angioedema: An overview. Immunol Allergy Clin North Am 2004;24:141-62.|
|51||Ghosh S, Haldar S. Therapeutic effect of doxepin in chronic idiopathic urticaria. Indian J Dermatol Venereol Leprol 1990;56:218-20.|
|52||Commens CA, Greaves MW. Cimetidine in chronic idiopathic urticaria: A randomized double blind study. Br J Dermatol 1978;99:675-9.|
|53||Spangler DL, Vanderpool GE, Carrol MS, Tinkelman DG. Terbutaline in the treatment of chronic urticaria. Ann Allergy 1980;45:246-7.|
|54||Bressler RB, Sowell K, Huston DP. Therapy of chronic idiopathic urticaria with nifedipine: Demonstration of beneficial effect in a double blinded, placebo controlled, cross-over trial. J Allergy Clin Immunol 1989;83:756-63.|
|55||Kaplan AP. Chronic urticaria and angioedema. N Engl J Med 2002;346:175-9.|
|56||Erbagci Z. The leucotriene receptor antagonist montelukast in the treatment of chronic idiopathic urticaria: A single blind, placebo controlled, crossover clinical study. J Allergy Clin Immunol 2002;110:484-8.|
|57||Anand MK, Nelson HS, Dreskin SC. A possible role of cyclooxygenase 2 inhibitors in the treatment of chronic urticaria. J Allergy Clin Immunol 2003;111:1133-6.|
|58||Toubi E, Blant A, Kessel A, et al . Low dose cyclosporine A in the treatment of severe chronic idiopathic urticaria. Allergy 1997;52:312-6.|
|59||Baskan EB, Tunali S, Turker T, Saricaoglu H. Comparison of short and long term cyclosporine A therapy in chronic idiopathic urticaria. J Dermatol Treat 2004;15;164-8.|
|60||O'Donnell BF, Barlow RJ, Kobza BA. Response of severe chronic urticaria to intravenous immunoglobulin (IVIG). Br J Dermatol 1994;131:32-4.|
|61||Grattan CE, Francis DM, Slater NG, Barlow RJ, Greaves MW. Plasmapheresis for severe unremitting chronic urticaria. Lancet 1992;339:1078-80.|
|62||Kessel A, Bamberger E, Toubi E. Tacrolimus in the treatment of severe chronic idiopathic urticaria an open-label prospective study. J Am Acad Dermatol 2005;52:145-8.|
|63||Gach JE, Sabroe RA, Greaves MW, Black AK. Methotrexate responsive chronic idiopathic urticaria: A report of two cases. Br J Dermatol 2001;145:340-3.|
|64||Hartmann K, Hani N, Hinrichs R, Hunzelmann N, Scharffetter-Kochanek K. Successful sulfasalazine treatment of severe chronic idiopathic urticaria associated with pressure urticaria (letter). Acta Dermatol Venereol 2001;81:71.|
|65||Boehm I, Bauer R, Bieber T. Urticaria treated with dapsone. Allergy 1999;54:765-6.|
|66||Bernstein JA, Garramone SM, Lower EG. Successful treatment of autoimmune chronic idiopathic urticaria with intravenous cyclophosphamide. Ann Allergy Asthma Immunol 2002;89:212-4.|
|67||Parsiew R, Pryce D, Ashworth J, Friedmann PS. Warfarin treatment of chronic idiopathic urticaria and angioedema. Clin Exp Allergy 2000;30:1161-5.|
|68||Staubach P, Onnen K, Vonend A, Metz M, Siebenhaar F, Tschentscher I, et al . Autologous whole blood injections to patients with chronic urticaria and a positive autologous serum skin test: A placebo-controlled trial. Dermatology 2006;212:150-9.|