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URTICARIA/ ANGIOEDEMA

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

Differential Diagnosis of Chronic Urticaria
REF: ACP PIER 2007

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

• acute - strawberries, pineapple, tomato, morphine, see extensive list below

• chronic (> 6 weeks) - 80-90% idiopathic, foods, SLE

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

   • chronic bacterial (sinus, dental, chest, gallbladder, UTI)

   • fungal (dermatophytosis, candidiasis)

   • viral (hepatitis, mono, coxsackie)

   • intestinal worms

   • malaria

   • Helicobacter pylori infection may be related to chronic urticaria; literature review of 10 studies of patients with urticaria at least 6 weeks, positive H. pylori testing, and other causes excluded; remission rates of urticaria were 31% for patients with successful H. pylori eradication, 22% for patients with unsuccessful H. pylori infection, and 13.5% for patients negative for H.pylori infection (J Am Acad Dermatol 2003 Nov;49(5):861 in QuickScan Reviews in Fam Pract 2004 May 20;29(10):9)

   • Mycoplasma pneumoniae infection associated with skin reactions in 3 patients within a single family, including erythema nodosum, anaphylactoid purpura, and acute urticaria (J Am Acad Dermatol 2007 Aug;57(2 Suppl):S33)

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)

        2009   

History for Chronic Urticaria

• Antihistamine and other medication use  -
  A rapid response to both over-the-counter and prescribed antihistamines is often claimed, but recurrences are often noted when medications are discontinued or omitted

• Duration of urticaria (>6 weeks) - longer than 6 weeks is consistent with a diagnosis of chronic urticaria

• Fever and other systemic symptoms
  such as weight loss, arthralgia, abdominal pain, fever, bodyache, or chest symptoms are not associated with CIU  (chronic idiopathic urticaria) but may instead suggest urticarial vasculitis

• Exacerbation of urticaria or initiation of urticaria by  physical stimuli as pressure, cold, heat, vibration, water, or sunlight
  Cold urticaria may be confirmed with an ice cube test, but the sensitivity of this test is incomplete.
  Cholinergic urticaria often occurs with heat, stress, and exertion and has a smaller papular appearance.
  Methacholine skin testing, a reputed diagnostic test for cholinergic urticaria, is neither sensitive nor practical to perform.
  Delayed pressure urticaria occurs 2-6 hours after pressure application

• Duration of urticarial lesions (<24 to 36 hours)

• Exacerbation concurrent with aspirin or NSAID use

• Exacerbation with certain foods -
  A food elimination diet carried out for over 5 days without improvement suggests the lack of a role for the avoided food. Suspected allergenic foods are not often confirmed by more objective testing

• Frequency and timing of hives (e.g., daily, perimenstrual, nocturnal)

• Presence of angioedema (described as nonpruritic swelling of the lips, eyes, hands)

• Presence of pruritus with the lesions

• Personal history of allergic disease

• Personal history of acute urticaria induced by ASA or NSAIDs

• Family history of hives : Familial clusters have been described in dermographic and cholinergic urticaria

Physical Exam for Chronic Urticaria

• Presence of angioedema : Often involves the eye, lips, or hands

• Skin exam for multiple wheals in typical shapes
  Wheals are typically plaques with expanding peripheral borders, but early or treated lesions may be macular, sometimes with central clearing

• Skin exam for dermographism
  Stroking of the skin with a blunt object such as a tongue blade will result in a typical wheal within 5 minutes

Laboratory and Other Studies for Chronic Urticaria

• ESR - Highly nonspecific but if persistently elevated indicates a more inflammatory process

• CRP  - As with ESR, but CRP is not affected by erythrocyte abnormalities

• Thyroid antibodies (autoantibodies to thyroid peroxidase/thyroglobulin/microsomes)  
  - TSH and free T4 measurements may also be considered because therapeutic interventions may be needed

• CBC/differential  - Ordering a CBC is useful for noting eosinophilia and other hematologic disorders (which may affect the ESR)

• IgE level  - May be elevated in serum sickness syndromes. Elevations also noted in coexisting atopic diseases

• RAST to specific allergens  - May be considered in evaluating coexisting atopic disease or if an avoidance measure is to be instituted

• C4 and other complement studies  - May be decreased with vasculitis, serum sickness syndromes, or presence of C4 null genes

• Skin biopsy  - Useful in confirming or establishing diagnosis of urticarial vasculitis

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.

        2009  

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.

   • Consider hydroxychloroquine, dapsone, colchicine, and sulfasalazine in patients with urticaria associated with inflammatory conditions (such as SLE or Sjögren's syndrome) or urticarial vasculitis.

   • Consider tacrolimus or cyclosporine in patients with severe CIU.

   • Consider modalities supported by limited data only in select patients or patients unresponsive to usual treatment.

Drug Treatment for Chronic Urticaria

H1 receptor antagonists

• Fexofenadine (Allegra) 120-180 mg/d
  Alleviates symptoms in most patients with chronic urticaria
  Mild anticholinergic effects.  Nonsedating

• Loratadine  (Claritin)10 mg/d
  Alleviates symptoms in most patients with chronic urticaria
  Mild anticholinergic effects.   Nonsedating

• Desloratadine (Clarinex) 5 mg/d  
  Alleviates symptoms in most patients with chronic urticaria
  Mild anticholinergic effects.  Nonsedating

• Cetirizine (Zyrtec) 10-20 mg/d
  Alleviates symptoms in most patients with chronic urticaria
  Mild anticholinergic effects . 10% sedation

• Diphenhydramine  (Benadryl) 25-50 mg q6h
  Available over-the-counter.  Sedating

• Hydroxyzine (Atarax) 25-50 mg q6h
  Related to cetirizine; can be given parentally.  Sedating

• Cyproheptadine (Periactin)  2-4 mg q6-8h
  Published efficacy in cold urticaria.  Sedating

• Chlorpheniramine (Chlor-Trimeton) 4 mg q4-6h
  Safer in pregnancy; available over the counter.  Sedating

• Tripelennamine 25-50 mg q6h
  Safer in pregnancy . Sedating

H2 receptor antagonists  

• Ranitidine (Zantac) 150 mg bid
  Useful in patients not responsive to H1 receptor blockade alone
  Few side effects.  Addition of H2 blockers possibly is more effective for dermographism.
  Effects are probably modest for chronic urticaria

• Cimetidine (Tagamet) 300 mg qid
  Useful in patients not responsive to H1 receptor blockade alone
  Significant drug-drug interactions.  Most frequently used H2 blocker in urticaria studies

• Famotidine  (Pepcid) 20 mg bid
  Useful in patients not responsive to H1 receptor blockade alone
  Few side effects.  Addition of H2 blockers possibly is more effective for dermographism.
  Effects are probably modest for chronic urticaria

Prednisone

• Glucocorticoid 40-60 mg/d as burst of 20-40 qod for suppressive long-term treatment
  Useful for short-term relief of symptoms, especially in refractory cases. Long-term treatment can be given as every-other-day doses Multiple side effects even with short-term use .
  Typically given for 7-10 days

• Prednisolone Glucocorticoid Dosepak (Medrol-Dosepak)  
  Useful for short-term relief of symptoms, especially in refractory cases.
  Long-term treatment can be given as every-other-day doses Multiple side effects even with short-term use Typically given for 7-10 days. Other steroids can be used at equivalent doses

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)

Cyclosporine
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.

        2009   

Medications for Urticaria      REF:  DynaMed 2009

Medications:

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

• Helicobacter pylori eradication in patients with idiopathic chronic urticaria beneficial in uncontrolled study; of 42 patients with idiopathic chronic urticaria, 23 found to have H. pylori infection; of patients in whom H. pylori was successfully eradicated, 88% had total or partial remission of urticaria (Dig Dis Sci 1998 Jun;43;1226 in QuickScan Reviews in Fam Pract 1999 Feb;23(11);10); at best, this study warrants a randomized controlled trial, placebo benefit and natural improvement over time can not be ruled out (DynaMed commentary)

• H. pylori eradication not very helpful in randomized trial; 125 patients with chronic urticaria screened for H. pylori with ELISA and urea breath tests, 78 (62%) had both tests positive (23 of whom consented to gastroscopy and had histologic confirmation), 65 H. pylori-positive patients randomized to eradication therapy vs. control group, 19% vs. 9% had complete remission of urticaria at 2-4 months, 10% vs. 0 had remission at 6-12 months (Acta Derm Venereol (Stockh) 1998;78;440 in QuickScan Reviews in Fam Pract 1999 Dec;24(9);24)

• Helicobacter pylori infection may be related to chronic urticaria (level 2 [mid-level] evidence); literature review of 10 studies of patients with urticaria at least 6 weeks, positive H. pylori testing, and other causes excluded; remission rates of urticaria were 31% for patients with successful H. pylori eradication, 22% for patients with unsuccessful H. pylori infection, and 13.5% for patients negative for H.pylori infection (J Am Acad Dermatol 2003 Nov;49(5):861 in QuickScan Reviews in Fam Pract 2004 May 20;29(10):9)

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)

        2009