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* Explain to patients that chronic urticaria spontaneously remits in a large proportion of cases.

Differential Diagnosis of Chronic Urticaria
Disease Characteristics Notes
Vasculitic urticaria ESR/CRP, longer duration of individual lesions, ±systemic symptoms, ±hypocomplementemia Biopsy diagnostic and clinical features distinct from other chronic urticarias
Serum sickness syndromes Similar to vasculitic urticaria; antigen or drug exposure apparent. Fever, adenopathy, arthralgias may be present IgE levels may be elevated. Prolonged drug reactions that manifest with recurrent hives for several weeks may be a variant of this
Recurrent immediate hypersensitivity reactions Some or all of features of anaphylaxis may present. Allergenic exposure usually apparent. Short time frame (usually within 2 hours) between symptom development and allergenic exposure (drug or food) Allergen-specific IgE, such as a food, sometimes detectable
Contact urticaria Urticarial wheals occur only in skin areas exposed to allergen or provocative agent. Allergenic exposure often apparent. Respiratory, nasal, or ocular symptoms may also be present Often due to pet exposure or latex. Allergen-specific IgE can be demonstrated usually
Insect bites Papules are not usually long lasting or as recurrent and only occur in exposed skin involved. A pruritic eruption occurring as a hypersensitivity reaction typically occurs on the exposed lower extremities following flea or other insect bites. Crops of small papules with a central punctum are classic May be difficult to diagnose without finding and eliminating offending insect
Prurigo/flushing syndromes Excoriations and erythema may be present, but no wheals are present at any time. Cholinergic erythema and cholinergic pruritus have the same triggers as cholinergic urticaria but without actual hive development Work-up for chronic flushing often unproductive. Patients with cholinergic erythema or cholinergic pruritus may evolve into cholinergic urticaria
Idiopathic anaphylaxis Hypotension, bronchospasm, and respiratory compromise are common in idiopathic anaphylaxis but not in chronic urticaria Tryptase and histamine levels are often elevated in anaphylaxis but are not increased in chronic urticaria
Polymorphous eruption of pregnancy Occurs during last trimester of pregnancy and terminates with delivery Also known as pruritic urticarial papules and plaques of pregnancy
Physical urticaria A subset of chronic urticaria that involves physical exposures Dermographism, cold urticaria, and cholinergic urticaria most common. Delayed pressure urticaria often associated with pain instead of itching and does not respond to H1 blockers
Parasitic infection Associated with significantly elevated eosinophils Strongyloides and filariasis may present with urticaria and angioedema. Serologic tests help diagnose these disorders. Trichinosis may manifest with periorbital edema
Nonbullous pemphigoid and prodromal bullous pemphigoid Often associated with blood eosinophilia, elevated IgE levels, and circulating antibasement membrane antibodies Skin biopsy examined by direct immunofluorescence shows IgG, C3, or both at the basement membrane
Prodromal dermatitis herpetiformis Face, trunk, and extremities involved, with numerous wheal-like papules Skin biopsy shows subepidermal blister formation along with IgA staining of the perilesional skin basement membrane. Transglutaminase and endomysial antibodies usually present
C3 = third component of complement; CRP = C-reactive protein; ESR = erythrocyte sedimentation rate; IgA = immunoglobulin A; IgE = immunoglobulin E; IgG = immunoglobulin G.

Causes of Urticaria:                                                                                      REF:  DynaMed 2009

Etiologic Classification of Urticaria

  1. foods - fish, shellfish, nuts, eggs, chocolate, wheat, pork, yeast, strawberries, tomatoes, cow's milk, cheese, celery, cabbage, peaches, grapes, alcohol

  2. food additives - salicylates, benzoates, penicillin, dyes e.g. tartrazine

  3. drugs - penicillin, aspirin, salicylates, sulfonamides, nonimmunologic release of histamine (morphine, codeine, polymyxin, dextran, curare, quinine)

  4. infectious

  5. inhalants - pollens, mold spores, animal danders, house dust, aerosols, volatile chemicals

  6. internal disease - serum sickness, SLE, hyperthyroidism, cancer, lymphoma, JRA (Still's disease), leukocytoclastic vasculitis, polycythemia vera (acne urticata - urticarial papule surrounded by vesicle), rheumatic fever

  7. physical urticarias - dermographism, pressure, cholinergic, solar, cold, heat, vibration, water (aquagenic)

  8. nonimmunologic contact urticaria - plants (nettles), animals (caterpillars, jellyfish), medications (cinnamic aldehyde, compound 40/80, dimethyl sulfoxide)

  9. immunologic or uncertain contact - ammonium persulfate (hair bleach), chemicals, foods, textiles, wood, saliva, cosmetics, perfumes

  10. skin disease - urticaria pigmentosa (mastocytosis), dermatitis herpetiformis, pemphigoid, amyloidosis

  11. pregnancy

  12. autosomal dominant (all rare) - hereditary angioedema, cholinergic urticaria with progressive nerve deafness and amyloidosis of the kidney, familial cold urticaria, vibratory urticaria

  13. autoimmune progesterone dermatitis (Clinical and Molecular Allergy 2004 Aug 2;2:10)

Causes of angioedema without urticaria

based on 929 consecutive patients with recurrent angioedema without urticaria at one outpatient clinic 1993-2003

153 (16%) lost to follow-up, causes reported for 776 cases

124 (16%) had angioedema related to external agents such as drug, insect bite or foodstuff

85 (11%) realted to ACE inhibitor

55 (7%) associated with autoimmune disease or infection

197 (25%) due to C1 inhibitor deficiency

315 (41%) had etiology unknown

Reference - CMAJ 2006 Oct 24;175(9):1065 EBSCOhost Full Text full-text, editorial can be found in CMAJ 2006 Oct 24;175(9):1083 EBSCOhost Full Text full-text

ACE inhibitors may be leading cause of airway compromise due to angioedema; retrospective chart review of 70 patients with airway obstruction due to angioedema, 45 patients (64%) used ACE inhibitors (Chest 2004 Aug;126(2):400 EBSCOhost Full Text in QuickScan Reviews in Fam Pract 2005 Feb 21;30(9):18)

angioedema due to enalapril (an ACE inhibitor) is uncommon; 86 patients (0.68%) had angioedema in randomized trial of 12,557 persons with hypertension treated with enalapril maleate 5-40 mg/day; risk factors for angioedema were black race (odds ratio 2.88), history of drug rash (odds ratio 3.78), age > 65 years (odds ratio 1.6), and seasonal allergies (odds ratio 1.79); angioedema more common after initiation of enalapril (3.6 per 1,000 patient-months) than later (0.4 per 1,000 patient-months) (Arch Intern Med 2005 Jul 25;165(14):1637)


History for Chronic Urticaria

Physical Exam for Chronic Urticaria

Laboratory and Other Studies for Chronic Urticaria

C4 = fourth component of complement; CBC = complete blood count; CRP = C-reactive protein; ESR = erythrocyte sedimentation rate; IgE = immunoglobulin E; RAST = radioallergosorbent test; TSH = thyrotropin.


Therapy for Chronic Urticaria

  1. Consider antihistamines to be the cornerstone of treatment for chronic urticaria.
    Administer nonsedating antihistamines for patients with chronic urticaria.

  2. Consider adding H2 receptor antagonists in patients not responding to H1 receptor antagonists alone.
    Consider adding cimetidine, ranitidine, or another H2 receptor blocker for chronic urticaria not responding to H1 blockade alone.

  3. Consider a trial of a leukotriene antagonist in patients who fail to respond to antihistamine treatment.
    In patients who are unresponsive to antihistaminic therapy, consider a course of montelukast or zafirlukast treatment.

  4. Consider a burst of corticosteroids for short-term suppression of urticaria.
    In patients who are unresponsive to antihistaminic therapy and are very uncomfortable, consider a brief course of oral corticosteroids.
    In rare severe cases, consider alternate-day corticosteroids for longer-term treatment.

  5. Consider short-acting sedating antihistamines in conjunction with nonsedating antihistamines.
    Consider adding diphenhydramine, hydroxyzine, or doxepin to nonsedating antihistamine treatment for breakthrough or refractory symptoms.

  6. Consider drugs used to treat rheumatic conditions and organ transplantation for certain patients with chronic urticaria and other agents in specific situations.

Drug Treatment for Chronic Urticaria

H1 receptor antagonists

H2 receptor antagonists  


Doxepin 20-30 mg/day 
Tricyclic antidepressant with antihistaminic effects 10-30 mg/d Same as diphenhydramine Anticholinergic effects, sedation Lower doses used for urticaria than for psychiatric conditions

Montelukast 10 mg/day
Leukotriene antagonist
May be useful in patients not responding to histamine receptor blockers Rare side effects There is one randomized, controlled trial showing possible advantage over H1 blockers in CIU patients who had exacerbations with ASA or food additives (17). Consider using in addition to H1 antagonists

Theophylline 200-400 mg/day  
Phosphodiesterase inhibitor
May be useful in patients not responding to histamine receptor blockers Nausea, headache, insomnia One pilot randomized, controlled study showed that sustained release theophylline added to cetirizine in antihistamine-refractory CIU patients resulted in a modest but statistically significant improvement but only after 1 month of treatment (72)

Nifedipine 20-60 mg/day  (oral)  
Calcium channel blocker
May be useful in patients not responding to histamine receptor blockers Headaches, weakness, dizziness, edema, flushing One very small randomized, controlled trial has shown an effect in patients who had not responded to H1 and H2 blockers. Side effects frequently observed (73)

Stanozolol 4 mg/day
Androgenic steroid
May be useful in patients not responding to histamine receptor blockers Elevations in liver function tests Study performed on patients “refractory” to conventional medical treatment. Conventional medical treatment was not defined (74)

Immunosuppressant 3-5 mg/kg·d (oral) May be useful in patients not responding to histamine receptor blockers Paresthesias, GI upset, headache, fatigue Benefit shown in one single randomized, controlled study on refractory CIU patients who also manifested positive autologous serum skin tests. Side effects frequently observed (75)
Also another randomized double-blinded study on refractory CIU patients showed improved severity scores and quality of life compared to placebo in those treated with cyclosporine given in tapering doses over 8-16 weeks (76)

ASA = acetylsalicylic acid; bid = twice daily; CIU = chronic idiopathic urticaria; GI = gastrointestinal; qod = every other day; qid = four times daily.


Medications for Urticaria      REF:  DynaMed 2009


antihistamines commonly used, steroids and epinephrine if severe

addition of H2 blocker to H1 antagonist helpful in acute urticaria; 91 adults presenting to emergency department with acute allergic reactions (mostly cutaneous manifestations, 12 with wheezing, 2 with hypotension) were all given diphenhydramine 50 mg IV and randomly given ranitidine 50 mg vs. placebo IV; 71% vs. 47% had resolution of angioedema and urticaria at 2 hours (NNT 5), 4% vs. 23% had additional diphenhydramine (NNT 6); no significant differences in use of steroids, epinephrine or hospitalization (Ann Emerg Med 2000 Nov;36(5):462 in J Watch 2000 Dec 15;20(24):194)

antihistamines effective for chronic urticaria

leukotriene antagonists, e.g. montelukast (Singulair)

chronic urticaria in patients with hypothyroidism, and even in euthyroid patients with antithyroid antibodies has been treated successfully with thyroxine (Cortlandt Forum 1996 Apr;9(4);151)

ketotifen used successfully in 1 adult patient with chronic urticaria refractory to prednisone, plasmapheresis and other medications; concern that chronic urticaria tends to eventually resolve so that case report not sufficient, ketotifen not FDA approved (Arch Dermatol 1997 Feb;133;147 in Pediatric Notes 1997 Feb 27;21(9);33)

cyclosporin A seems effective in small uncontrolled studies (Immunopharmacol Immunotoxicol 2001 May;23(2):205 EBSCOhost Full Text and Br J Dermatol 2000 Aug;143(2):365 EBSCOhost Full Text in Cortlandt Forum 2003 Feb;16(2):65)

Helicobacter pylori eradication not likely to be effective

COX-2 inhibitors may be safe in patients with NSAID-induced urticaria (level 2 [mid-level] evidence); 36 patients with chronic idiopathic urticaria and NSAID sensitivity underwent aspirin challenge with up to 500 mg, 18 (50%) had aspirin-induced skin eruption; aspirin-sensitive patients were randomized to rofexocib up to 37.5 mg vs. celecoxib up to 300 mg, none had skin eruptions; 7 patients given naproxen sodium 500 mg and 5 had urticaria (Arch Dermatol 2003 Dec;139(12):1577 in JAMA 2004 Mar 3;291(9):1050)

allergen immunotherapy not effective for urticaria, based on unreferenced statement in review article (Am Fam Physician 2004 Aug 15;70(4):689)

sulfasalazine reported to be associated with significant improvement in recalcitrant chronic idiopathic urticaria (level 3 [lacking direct] evidence)