diagnostic approach and treatment of urticaria and angiodema : an update jonathan a. bernstein, m.d....
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Diagnostic Approach and Treatment of Urticaria and
Angiodema: An Update
Jonathan A. Bernstein, M.D.Professor of Clinical Medicine
Division of Immunology/Allergy Section
Conflict of Interest Disclosures:
Jonathan A. Bernstein, MD FACAAI, FAAAAI
Employment: University of Cincinnati and Bernstein Allergy Group and Clinical ResearchFinancial: CSL Behring; Dyax; Shire; Teva, ViropharmaResearch: CSL Behring; Dyax; Pharming; Shire; Viropharma, NovartisLegal: Nothing to discloseOrganizational: AAAAI; ACAAI; AFIGifts: Nothing to discloseOther: Editor in Chief Journal of Asthma
Objectives:
Upon completion of this lecture the participant should be able to:
• Identify the differential diagnosis of urticaria and angioedema• Explain the appropriate laboratory evaluation of urticaria and
angioedema• Describe the conventional treatment approach for urticaria
and angioedema
WORLD ALLERGY ORGANIZATION POSITION PAPERDIAGNOSIS AND TREATMENT of URTICARIA AND
ANGIOEDEMA: A WORLDWIDE PERSPECTIVE
Mario Sánchez-Borges 1, Riccardo Asero 2, Ignacio Ansotegui 3, Ilaria Baiardini 4, Jonathan A. Bernstein 5, G Walter Canonica 4, Richard Gower 6, David A Kahn 7, Allen P Kaplan 8, Connie Katelaris 9, Marcus Maurer 10, Hae Sim Park 11, Paul Potter 12, Sarbjit Saini 13, Paolo Tassinari 14, Alberto Tedeschi 15, Young Min Ye 11, Torsten Zuberbier 10
The Diagnosis and Management of Acute and Chronic Urticaria: 2012 Update
Chief EditorsJonathan Bernstein, MD and David Lang, MD
Workgroup Contributors Timothy Craig, DO; David Dreyfus, MD; Fred Hsieh, MD;
David Khan, MD; Javed Sheikh, MD; David Weldon, MD; and Bruce Zuraw, MD
Task Force Reviewers David I. Bernstein, MD; Joann Blessing-Moore, MD; Linda Cox, MD;
Richard A. Nicklas, MD; John Oppenheimer, MD; Jay M. Portnoy, MD; Christopher R. Randolph, MD; Diane E. Schuller, MD;
Sheldon L. Spector, MD; Stephen A. Tilles, MD; and Dana Wallace, MD
Features of Urticaria
Raised, pink/erythematous skin lesions that are markedly pruritic; lesions range from a few millimeters to several centimeters in size and may coalesce
Evanescent; old lesions go and new ones come over 24 hours leaving no scarring
Generally worsened by scratchingAny area of the body may be involved; most
common areas are the perioral and periorbital regions, tongue, genitalia and extremities
Prevalence of Urticaria
Estimated to occur in 15-23% of the U.S. population
Up to 40% of patients who have chronic urticaria longer than six months will still have urticaria 10 years later
Approximately 40% of patients with chronic urticaria have angioedema
Prevalence of Urticaria With and Without Angioedema
Urticaria
Acute urticaria refers to hives lasting less than six weeks; in approximately 15-20% of cases an inciting cause can be identified
Chronic urticaria refers to hives lasting longer than 6-8 weeks; identification of a cause is less than 5%
Differential Diagnosis: Immunologic Causes More Often Responsible for Acute Urticaria
FoodsMany drugs Insect stingsTransfusion reactionsContactants/Inhalants (rare)
Differential Diagnosis: Non-Immunologic Causes More Often Responsible for Chronic Urticaria
Physical hives (i.e., dermatographism, pressure, solar, cold…)Hereditary (i.e., cold, heat, vibratory, porphyria, C3b
inactivator deficiency…)VasculitisNeoplasmsInfectionsEndocrineDrugs (i.e., aspirin/NSAIDs-exacerbate hives in up to 30% of
cases)Psychologic? More a myth than fact
Most CU is Idiopathic•SUMMARY STATEMENT 13: Evaluation of a patient with CU should involve consideration of various possible causes. Most cases do not have an identifiable cause [C]
Features of Physical UrticariaType Age (yrs) Clinical Features Angio-
edemaDiagnostic Test
Dermatographism 20-50 Linear lesions No Light stroking of skin; + transfer factor
Cold (primary vs. secondary)
10-40 Itchy, pale lesions(5% with cryos)
Yes 5-10 minute ice-cube test; + transfer factor
Cholinergic (heat bumps)
10-50 Itchy, monomorphic pale or pink lesions
Yes Exercise or hot shower; + transfer factor
Pressure 20-50 Large painful or itchy lesions
No Dermographometer; application of pressure to skin or Sand bag test 15 lb weight for 15 minutes
Solar 20-50 Itchy pale or red swelling Yes Irradiation by a solar simulator;+ transfer factor
sitesearch: exact match:
© 2002 by DermIS - Dermatology Information System
sitesearch: exact match:
© 2002 by DermIS - Dermatology Information System
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Familial Cold Urticaria (aka. Familial Cold Autoinflammatory Syndrome)
Autosomal dominantCharacterized by episodic urticaria, arthralgias, fever and
conjunctivitis after exposure to coldSame genetic locus on chromosome 1q44 as Muckle-Wells
syndrome (an autosomal dominant periodic fever syndrome associated with hives and sensorineural hearing loss)
Cryopyrin gene preferentially expressed in families with this disorder; significant homology to the Nod2 gene implicated in Crohn’s disease
Hoffman HM, et.al. Nat Genet 2001; 29:301-5.
© Copyright protected - Do not copy without the editors' written permission.
lesion description additional description
opaleness
owheal opale red opolycyclic
opurpura
Urticarial Vasculitis:Features That Differentiate It From CIU
Feature Chronic urticaria Urticarial vasculitis
Wheal duration <24 hr >24 hr (not always true)
Purpura/pain/hyper- pigmentation
No Yes
Systemic signs Usually none Yes
Laboratory findings Usually normal Increased WSR, Acute Phase Reactants; Decreased C3/C4
Leukocytoclasia or extravasation of RBCs
No Yes
Response to antihistamines Yes Sometimes
Chronic Urticaria: The Evaluation
History and Physical Examination1.Onset (e.g. timing of symptoms with any change in medication or other exposures).2.Frequency, duration, severity, and localization of wheals and itching.3.Dependence of symptoms on the time of day, day of the week, season, menstrual cycle, or other pattern.4.Known precipitating factors of urticaria (e.g. physical stimuli, exertion, stress, food, medications).5.Relation of Urticaria to Occupation and leisure activities.6.Associated angioedema, systemic manifestations (headache, joint pain, gastrointestinal symptoms, etc.)7.Known allergies, intolerances, infections, systemic illnesses or other possible causes. 8.Family history of urticaria and atopy.9.Degree of impairment of quality of life.10.Response to prior treatment.11.General physical examination.
Laboratory Evaluation• Routine evaluation: There is no consensus regarding the appropriate tests
which should routinely be performed for patients with CU without atypical features by history or physical exam.
• Commonly performed tests are: • CBC with differential• Sedimentation rate and/or C-reactive protein.
• Some clinicians routinely perform:• Chemistry panel• Hepatic panel• TSH• Anti-microsomal antibodies, anti-thyroglobulin antibodies
Evaluation (Cont.)Possible additional evaluation warranted by elements of history or physical exam
which would make these tests appropriate:Functional autoantibody assay (for autoantibodies to FcεRIά) and/or autologous serum or plasma
skin testingComplement system: e.g. C3, C4, and CH50
Stool analysis for ova and parasitesH. pylori workup (limited experimental evidence to recommend this)Hepatitis B and C workupChest radiograph and/or other imaging studiesAntinuclear antibody (ANA)Rheumatoid factorCryoglobulin levelsSerologic and/or skin testing for immediate hypersensitivityPhysical challenge testsSkin biopsyUrinalysis
Recommendations on Specific Tests
• Testing not indicated on routine basis– Autoimmune serology (SS #15)– Testing for H pylori or celiac disease (SS #19)– Thyroid Autoantibodies (SS #30)– CU Autoantibody Tests (SS #31)– Skin Biopsy (SS #34)– Hypersensitivity Testing (e.g. skin testing) (SS # 35)
• Retrospective study to investigate the proportion of abnormal test results in patients with CU leading to a change in management and in outcomes of care
• 356 CU pts seen at Cleveland Clinic
Tarbox JA et al. Ann Allergy Asthma Immunol 2011;107:239 –243.
Tarbox JA et al. Ann Allergy Asthma Immunol 2011;107:239 –243.
17% of 1,872 ordered tests were abnormal
Tarbox JA et al. Ann Allergy Asthma Immunol 2011;107:239 –243.
1 patient with hypothyroidism with normal TSH and elevated microsomal AB responded to higher dose thyroxine
1/356 (0.28%) benefitted from testing!
Diagnostic Testing in CU• SUMMARY STATEMENT 29: After a thorough history and physical
examination, no diagnostic testing may be appropriate for some patients with CU; however, limited routine lab testing may be performed to exclude underlying causes. Targeted lab testing based on clinical suspicion is appropriate. Extensive routine testing for exogenous and rare causes of CU, or immediate hypersensitivity skin testing for inhalants or foods, is not warranted. Routine laboratory testing in patients with CU, whose history and physical examination lacks atypical features, rarely yields clinically significant findings.[C]
Conventional Therapy of Chronic Urticaria
Antihistamines in Chronic Urticaria
• Nearly all symptoms of urticaria are primarily mediated by H1-receptors located on nerves and endothelial cells
• H1 antagonists mainstay of therapy for most all chronic urticaria
International ConsensusMeeting on Urticaria
• “The recommended first line treatment is new generation, nonsedating H1-antihistamines.”
• level of evidence: high quality• strength of recommendation: strong
Allergy 2009;64:1427-43.
High Dose Antihistamines in CU
• Cetirizine: conflicting studies• Fexofenadine: no difference between 60 mg,
120 mg and 240 mg twice a day• Desloratadine
– 20 mg > 5 mg in cold urticaria
• Levocetirizine and desloratadine– Higher doses betterKavosh ER, Khan DA. Am J Clin Dermatol 2011 Dec 1;12(6):361-76.
High Dose Antihistamines in CU
Staevska M, Popov T et al. J Allergy Clin Immunol 2010;125:676-82.
Response to Antihistamines in CU• Study of 390 urticaria patients from general
dermatology or urticaria clinics, majority of which had CU
• 297 had evaluable treatment outcomes with antihistamines– 58% had good response– 20% had partial relief– 22% had no benefit
• More likely to have physical urticaria or NSAID exacerbated CU
Humphreys F et al. Br J Derm 1998: 138: 635-638.
Antihistamine Resistance in CU• Definition
– Fail despite high doses of antihistamines
– Unable to tolerate higher doses of antihistamines
Systemic Corticosteroids in CU
• Systemic corticosteroids are frequently used in patients with CU refractory to antihistamine therapy
• No controlled trials have demonstrated the efficacy of systemic corticosteroids in CU
• “systemic corticosteroids should be avoided for long-term treatment of CU, since dosages necessary to suppress symptoms are usually high with significant adverse effects” (International Consensus Meeting on Urticaria)
Allergy 2009;64:1427-43.
Alternative Agents in Urticaria
• Alternative agents for CU are therapies used for patients failing conventional (i.e. antihistamine) therapy
• Alternative agents have a variety of mechanisms
• Antiinflammatory• Immunosuppressant• Immunomodulatory• other
Evidence for Alternative Therapies in CU
• Overall the evidence for most alternative therapies is weak
• Few agents have well designed randomized placebo-controlled studies
• Most studies have small number of participants
Khan DA. In: Maibach HI, Gorouhi F ed. Evidence Based Dermatology 2nd ed. 2011
Natural Course/Prognosis of Chronic UrticariaKozel MM, et.al. J Am Acad Dermatol 2001;45:387-91
220 adults with chronic urticaria were followed prospectively for 1-3 years at the University of Amsterdam
After one year, 35% were free of all symptoms and 30% had decreased symptoms
47% of patients with CIU had spontaneous remission over 3 years compared to only 16% who had a component of physical urticaria
Conclusion: Prognosis for spontaneous remission of chronic urticaria is reasonable with the exception of the subgroup with a physical component
Conclusions
• Chronic Urticaria and/or Angioedema is common• A thorough history and physical exam is essential• Should consider a broad differential diagnosis • The initial laboratory evaluation of patients should
be limited unless history dictates otherwise• Outcomes are variable but generally good if
appropriate evaluation and treatment algorithms are followed
