A BEE of Hives Disclosure Urticaria

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A BEE of Hives Disclosure Urticaria Powered By Docstoc
         A, BEE, C’s of Hives
               Ted Rosen, MD                            • No conflict of interest to disclose in
          Professor of Dermatology                                             presentation.
                                                          relationship to this presentation
          Baylor College of Medicine

           Learning objectives                                                          Urticaria
Following this presentation you should be able to:
• Distinguish varying forms of physical urticaria        Definition
• Formulate a differential diagnosis and treatment       A wheal and flare reaction initiated at the level
  plan for acute urticaria                               of the small venules of the skin in response to
• Describe the role of autoimmunity as a                 substances that cause: vasodilatation,
     th     i     h i
  pathogenic mechanism for chronic urticaria
                           f   h    i   ti i             increased vascular permeability, and
• Describe a therapeutic approach for patients           stimulate type C unmyelinated afferent
  with severe chronic idiopathic or chronic              cutaneous neurons releasing neuropeptides
  autoimmune urticaria.                                  (leading an axon reflex)
• Recognize and manage urticarial vasculitis

                                                     Guldbakke KK, Khachemoune A. Cutis. 79:41-9, 2007.


    Urticaria: Classification Scheme                                                                 Classification of “Ordinary” Urticaria
 “Urticaria” is an umbrella term = Diverse entities
                                                                                                     • Conventionally ordinary urticaria is broadly
•    Ordinary urticaria: Acute, Chronic                                                                divided into acute and chronic
•    Autoimmunue chronic urticaria                                                                   • Acute urticaria typically has been present
•    Physical urticaria: Mechanical, Thermal, Other                                                    6 weeks or less, while Chronic urticaria is
•    Angioedema: Idiopathic, Drug, C1 esterase def                                                     conventionally defined as daily or almost
•    Contact ti i
     C t t urticaria                                                                                   d il urticarial eruptions occurring for 6
                                                                                                       daily   i i l         i          i f
•    Urticarial vasculitis                                                                             weeks or more
•    Auto-inflammatory syndromes                                                                     • Chronic urticaria is further subclassified
     Hereditary (Cryopyrin Associated Syndromes)                                                       into several distinct entities
     Acquired (Schnitzler Syndrome)

Scheme of: Grattan CE, Humphreys F, Br J Dermatol 157:1116-1123, 2007

       Classification of Chronic Urticaria

                                                                                                         Idiopathic = Idiot-pathetic
    Urticarial           Physical Ordinary y                   Contact        Schnitzler’s
    vasculitis           urticaria chronic                    urticaria*       syndrome
                                   urticaria                                  and others                    We are just too uninformed to
                 Autoimmune                                   Idiopathic                                    really know what’s going on!
                   urticaria                               chronic urticaria

                                                             *Contact urticaria classified both as
                                                             acute and chronic by various experts

• Urticaria affects from 1% to up to 25%
  of the population at some time in a lifetime
• Transitory (individual lesions < 24h duration)
• Itching is the predominant symptom
• No desquamation, rarely affects mucous
• Associated with angioedema (up to 40% of cases)
• Acute (< 6 weeks) constitutes 75% of cases
• Chronic (> 6 weeks) constitutes 25% of cases
Sheldon J. Allergy. 25:525-30, 1954
Cooper KD. J Am Acad Dermatol 25:166-74, 1991
Greaves MW. N Engl J Med. 332:1767-1772,1995
Poonawalla T, Kelly B. Am J Clin Dermatol. 10:9-21, 2009
        Urticaria: Natural History                                                               My Mom: 91 and Feisty (9/23/09)
• Given acute episode of urticaria, what
  is likely to happen?
• ~50% will resolve in 6 months
• >50% will resolve in 12 months or less
• 20% will resolve in 12-36 months
• 20% will resolve in 36-60 months
• Some may resolve even after 25 years!
• Recurrence rate is high: 25-40%

Champion RH, Roberts SO, Carpenter RG, et al. Br J Dermatol. 81:588-597, 1969. (Classic Study)
Negro-Alvarez JM. Allergol Immunopathol (Madr). 25:36-51,1997.
Negro-Alvarez JM. Allergol Immunopathol (Madr). 29:129-132, 2001.

       Pathophysiology of Urticaria
• Most types of urticaria are due to activation
  of dermal mast cells, although basophils
  may also be involved
• Release of histamine and other mediators
             eicosanoids, proteases
  (including eicosanoids proteases, and
  cytokines) causes local vasodilation and
  vasopermeability, fibrin deposition, very mild
  perivascular mixed cellular infiltration
• Histologically, there is minimal endothelial
  swelling and no leukocytoclasis

                                                                                                  Experimental Hive Formation
                                                                                                 • Wheals will follow intradermal injection of:

                                                                                                 • Histamine

                                                                                                 • Leukotrienes C and D

                                                                                                 • Platelet activating factor (PAF)

                                                                                                 • Bradykinin

                                                                                                 • Substance P
             Beware: “Pseudourticaria”                                                                                            Urticarial Mimics
  •    Maculopapular exanthems (viral, drug rashes)
  •    Urticaria-like dermatitis (nummular eczema)
  •    Erythema multiforme
  •    Insect bite reactions (“papular urticaria”)
  •    Leukocytoclastic vasculitis
  •    Polymorphic light eruption
  •    Rarely: lymphoma cutis
  •    Some autoinflammatory syndromes

  Brodell LA, Beck, LA.. Differential diagnosis of urticaria. Ann Allergy Asthma Immunol. 100:181-8, 2008

      Urticaria Requires Medical Care
 •    Persisting beyond 6 weeks
 •    Related to allergy which can be alleviated
 •    Associated with angioedema
 •    Associated with bruising or discoloration
                              g                                                                                              ACUTE URTICARIA
 •    Associated with blistering
 •    Associated with fever or other symptoms
 •    Non-responsive to antihistamines
 •    Non-itchy in nature
  Guldbakke KK, Khachemoune A. Cutis. 79:41-9, 2007.

                               Acute urticaria                                                                         Causes of Acute Urticaria
        • 75% of all cases of urticaria                                                                     • Viral infections, particularly in children. In
                                                                                                              adults: prodrome of Hepatitis B, infectious
        • All ages; is common in childhood
                                                                                                              mononucleosis (EBV), HCV active infection
        • Abrupt onset of urticarial eruption
                                                                                                            • Drugs (NSAIDS, penicillin derivatives, sulfa
          usually pruritic and widespread
                                                                                                              drugs, anticonvulsants, radiocontrast media)
        • Angioedema common                                                                                 • Foods non–allergic (e.g., scombroid fish
        • Systemic symptoms (malaise, anorexia)                                                               poisoning) and allergic (IgE–mediated) (e.g.,
          also common, depending on cause                                                                     nuts, shellfish)
        • Duration: usually hours or days                                                                   • Immunization vaccines: MMR, tetanus toxoid
        • Often identifiable cause by history                                                               • Immediate contactants
Zuberbier T, Ifflander J, Semmler C, et. al. Acta Derm Venereol 76:295-297, 1996.
                                                                                                            Frigas A, Park MA. Am J Clin Dermatol. 10:239-50, 2009
Deacock DJ. Clin Exp Immunol. 153:151-61, 2008.
            Acute Urticaria with HBV                                                        Investigation of Acute Urticaria
                                                                                          • Many cases require no investigation because
                                                                                            the cause is evident to both the patient and
                                                                                            the doctor alike
                                                                                          • Good history will lead to limited lab testing
                                                                                            which often discloses the etiology
                                                                                          • Skin prick tests may support the diagnosis
                                                                                            (but avoid in severely affected patients, and
                                                                                            in patients with current angioedema or a
                                                                                            history of angioedema)
                                                                                          • Serum IgE testing may also help confirm the
                                                                                            suspected culprit

  Acute Urticaria: Prognosis and Treatment                                                                           Food Allergy
• Many attacks of acute urticaria are solitary,
                                                                                             • Mediated by binding of allergens that
  and the cause is evident and avoidable
                                                                                               survive digestion, and delivered to the
• Resolves with time                                                                           skin to interact with IgE on cutaneous
• Facial / labial / buccal angioedema responds to                                              mast cells
  SQ adrenaline administered every 10-15 min                                                 • Can be diagnosed by skin test or RAST
• Severe oropharyngeal angioedema should                                                       assay – result must be correlated with
  prompt overnight admission                                                                   history and be reproducible
• Chlorpheniramine 4 mg or diphenhydramine 50                                                • Double-blind oral challenge represents
  mg by injection or by mouth usually sufficient                                               the definitive test for diagnosis
  to suppress even widespread urticaria. Newer                                               • Best therapy: AVOIDANCE
  H1 antihistamines are also be useful.
Zuberbier T, Greaves MW, Juhlin L, et. al. J Invest Dermatol Symp Proc 6:128-131, 2001.         Lack G. Clinical practice: Food allergy. N Engl J Med 359:1252-1260, 2008
Frigas A, Park MA. Am J Clin Dermatol. 10:239-50, 2009

                    A bag of peanuts….                                                          Food “Pseudoallergens”
                                                                                          • 60+% of patients with hives suspect
                                                                                            food as the etiologic factor, but in only
                                                                                            1% of adults is true IgE food allergy
                                                                                            implicated! Zuberbier T. J Investig Dermatol Symp Proc. 6:132-4, 2001
                                                                                            Pseudoallergens, however, may be very
                                                                                          • P      d ll                h                               b
                                                                                            important provoking factors: additives
                                                                                            (color, preservative, flavor), herbs/spices,
                                                                                            some fruits (tomato); > chronic urticaria
                                                                                          • Diet devoid of these substances may
                                                                                            be beneficial Magerl M, Pisarevskaja D. Allergy 65:78, 2010
                            Drug Reactions                                              Acute Urticaria: Amoxicillin
• Drug or drug metabolite may cause hives by
  interaction with IgE antibody on cutaneous
  mast cells Example: Penicillin allergy
• Non-IgE mediated reactions that depend on
  drug metabolism with resultant mast cell
  activation or direct interaction with resultant
  mast cell activation or direct interaction with
  small venules Examples: NSAID reactions
  due to excessive leukotrienes, opiate induced
  direct mast cell degranulation, radiocontrast
  activation of complement leading to mast cell
Jurakic R, Marinovic B, Lipozencic J. Acta Dermatovenerol Croat. 17:54-69, 2009.
Tan EK, Grattan CE. Expert Opin Drug Saf. 3:471-84, 2004

                          Contact Urticaria                                               Causes of Contact Urticaria
                                                                                                     (Often Occupational)
   • Eliciting substance causes local wheal
     and flare within minutes of application                                               Immunological:                     Non-immunological:
     to skin                                                                       •   House dust mite                   •   Foods, especially fish
                                                                                   •   Dairy products                    •   Fragrances, flavorings
   • May be associated with systemic                                               •   Fruits                            •   Medicaments
     symptoms: rhinitis, conjunctivitis,                                           •   Nuts, especially peanuts          •   Animals: caterpillars, jellyfish
     bronchospasm, angioedema,
     bronchospasm angioedema anaphylaxis                                           •   Meats                             •   Plants, esp. nettles, corals
   • Classified as immunological and                                               •   Sea foods                         •   Preservatives, antiseptics
                                                                                   •   Vegetables, esp. garlic, onion    •   Ammonium persulphate
                                                                                   •   Fragrances
   • Release of histamine and prostaglandin                                        •   Hair care products
     D2 from dermal mast cells                                                     •   Medicaments, esp. antibiotics
                                                                                   •   Plant products, esp. latex
  Kim E, Maibach H. Contact Urticaria. In: Urticaria and Angioedema.
  Eds. M.W. Greaves and A.P. Kaplan. Marcel Dekker, New York. 2004. P. 149-169.
  Amaro C, Goossens A. Contact Dermatitis. 58:67-75, 2008.

    Contact Urticaria: Io Caterpillar                                                  Contact Urticaria: “Lip Plumper”
                  Blocked by Anti-histamines

                                                                                                       Kissed on the cheek by mother who
                                                                                                       was using an OTC “lip plumper”
        Contact Urticaria: Investigation                                                Contact Urticaria: Treatment
 • Open elicitation: Apply suspected agent to normal skin
 • Prick test in normal skin:
   Start with high dilution; include saline and histamine
   controls; risk management (anaphylaxis): patient to                              • Treatment consists of identification
   remain on premises for 2 hours, physician and
   resuscitation equipment on hand throughout
                                                                                      of culprit, avoidance and patient
 • Scratch test in normal skin:                                                       education Kim E. Maibach H. Clin Dermatol. 21:346-352, 2003
   Scratch skin lightly through drop of a high dilution of
   candidate culprit; controls and risk management as
 • Latex contact allergy due to rubber gloves:
   Place fragment of rubber glove in 5ml warm water and
   stir 20min, then use water for skin testing as above

                                                                                  Physical Urticaria: Classification
                                                                                   • Symptomatic dermographism (factitious urticaria)
                                                                                   • Pressure urticaria
                                                                                   • Cholinergic urticaria

                  CHRONIC URTICARIA                                                  Less common
                                                                                   • Cold urticaria
                                                                                   • Solar urticaria
                                                                                   • Heat urticaria
                                                                                   • Aquagenic urticaria
                                                                                   • Vibratory urticaria and angioedema

                                                                                            Dice JP. Physical urticaria. Immunol Allergy Clin North Am. 24:225-46, 2004

Characteristics of Physical Urticaria                                              Symptomatic Dermatographism
                                                                               • Most common physical urticaria
          • Hives last less than 2 hours                                       • Generalized pruritus and linear red wheals,
          • Stimulus (e.g., ice cube test, warm                                  aggravated naturally by scratching, rubbing,
            water, exercise, scratching) reliably                                and wearing of tight or coarse clothing
            reproduces clinical situation
          • Treated readily with antihistamines                                • Firm stroking of uninvolved skin causes almost
            but may require high doses                                           immediate linear red wheal and itch
          • Do not respond well to corticosteroids                             • Mucous membranes unaffected; no angioedema
                                                                               • Treatment: low sedation H1 antihistamines
                                                                               • Resistant: NB-UVB Borzova E, et al. J AM Acad Dermatol 59:752-57, 2008
                                                                               Greaves M, Sundergaard. Arch Dermatol 101:418-425, 1970.
                                                                               Wong RC, Fairley JA, Ellis CN. J Am Acad Dermatol. 11:643-52, 1984 (Review)
Soter N. Physical urticaria/angioedema. Semin Dermatol 6:302-320, 1987.        Shiarpe GR, Shuster S. Br J Dermatol 129:575-579, 1993.
Dice JP. Physical urticaria. Immunol Allergy Clin North Am. 24:225-46, 2004.   Greaves MW. J Allergy Clin Immunol 105:664, 2000
                          Dermatographism                                                             Dermatographism

                        Dermatographism                                                                  Pressure urticaria
                                                                                • Concurrent with chronic ordinary urticaria in
                                                                                  about 40% of cases
                                                                                • Common distribution sites: shoulders, waist,
                                                                                  soles, palms, buttocks
                                                                                • Swellings are frequently of long duration
                                                                                  (> 24h), often tender and painful; arthralgia
                                                                                  common; steroids better than antihistamines
                                                                                • Diagnosis: firm application of tip of a 3mm
                                                                                  diameter rod to uninvolved skin for 2 min;
                                                                                  positive: persistent firm red papule in 3-5 hrs
                                                                                Estes S, Yung C. J Am Acad Dermatol 5:25-31, 1981.
                                                                                Dover JS, Kobza Black A, Milford WA, et. al. J Am Acad Dermatol 18:1289-1298, 1988.
                                                                                Barlow RJ, Warburton F, Watson K, et al. J Am Acad Dermatol 29:954-958, 1993.

                      Cholinergic Urticaria                                                         Cholinergic Urticaria
 • Very common in older children, young adults
 • Pruritic and symmetric, red micropapular
   (1-2 mm) rash on neck, trunk, limbs after
   exercise, heat, emotional episode
 • Associated bronchospasm in more severe
   cases but only rarely angioedema
 • Dx: exercise challenge usually elicits a
   positive response. Heat challenge may also
   evoke the rash
 • Responds to H1 antihistamines, anabolic
   steroids (eg, danazol) in severe cases
Grant RT, Pearson RS, Comeau WJ. Clin Sci 2;253-272, 1936.
Soter NA, Wasserman SI, Austen KF, et. al. N Eng J Med 302:604-608, 1980
Fukunaga A, Bito T, Tsura K, et. al. J Allergy Clin Immunol 116:397-402, 2003
                     Cholinergic Urticaria                                                                   Cold Urticaria
                 Doing Dishes in Hot Water                                  • Redness, whealing itching on skin exposed to
                                                                              cold surfaces, water, air; occurs re-warming
                                                                            • Angioedema can occur e.g., lips, tongue after
                                                                              sucking an iced-lollipop; 20% atopic as well
                                                                            • If generalized (e.g. cold sea bathing), can be life
                                                                              threatening (syncope)
                                                                            • Diagnosis: icepack or ice cube in saran wrap
                                                                              on uninvolved skin for 15 min, remove and
                                                                              inspect site for wheal 5-15 min after removal
                                                                            • Responds to avoidance + H1 antihistamines.
                                                                              “Cold desensitization” is effective
                                                                            Houser D, Arbesman C, Ito K, et. al. Am J Med 49:23-33, 1970.
                                                                            Wanderer A, St-Pierre J, Ellis E. Arch Dermatol 13:1375-1377, 1977.
                                                                            Kaplan A, Garofalo J, Sigler R, et. al. N Eng J Med 305:1074-1077, 1981.

                                                                                                Cold Urticaria
                            Cold Urticaria
                                                                                         Spilled Cold Beer on Hand

                     Boyce JA. J Allergy Clin Immunol. 117:1415-8, 2006.

               Rare Physical Urticaria                                                         Rare Physical Urticaria
• Solar urticaria                                                               • Aquagenic urticaria
  Diagnosis: expose skin to direct sunlight, LCD                                  Diagnosis: expose face, neck upper trunk skin to
  projector lamp; a local pruritic wheal and flare                                tepid water (eg squeezing a sponge); elicits a
  reaction denotes a positive result                                              transitory pruritic erythematous maculopapular
                                                                                  eruption; Dyspnea and wheezing may accompany
  Treatment: avoidance, H1 antihistamines, light                                • Vibratory urticaria and angioedema
  tolerance treatment in selected patients                                        Diagnosis: vibrate forearm with a tuning fork or
• Heat contact urticaria                                                          rub a towel vigorously across the back (assuming
                                                                                  no dermatographism). Usually occupational
  Diagnosis: place warm beaker base (45o C) on
  clinically uninvolved skin for 5 min; a local pruritic
                                                                                    Treatment: avoidance and H1 antihistamines
  wheal and flare reaction denotes a positive result
  Treatment: avoidance; H1 antihistamine
  “heat desensitization” may be beneficial
Kobza-Black A. In: Urticaria and Angioedema. Eds. M.W. Greaves
and A.P. Kaplan. Marcel Dekker Inc. New York, 2004, P. 171-214.            Kobza-Black A. In: Urticaria and Angioedema. Eds. M.W. Greaves and A.P. Kaplan.
Botto NC, Warshaw E. J Am Acad Dermatol 59:909-920, 2008                   Marcel Dekker Inc. New York, 2004, P. 171-214.
                            Chronic Urticaria                                          Chronic Ordinary Urticaria
     1)   Chronic ordinary urticaria                                           The basic cause and pathogenesis of many
             a) Idiopathic (60-75% of all chronic urticaria)                   cases of chronic ordinary urticaria still
             b) Autoimmune
                                                                               remains unclear, but the weight of available
     2) Cutaneous urticarial vasculitis                                        evidence indicates that the following are
           a) Idiopathic                                                       not causative:
              A     i t d /          ti ti    di
           b) Associated w/ connective tissue diseases                           Food ll
                                                                               • F d allergy
           c) Hypocomplementemic urticarial vasculitis
                                                                               • Chronic infections (including Helicobacter pylori)
       3) Genetic autoinflammatory syndromes                                   • “Stress”
                                                                               • Drug allergy
       4) Miscellaneous e.g., Schnitzler’s Syndrome
                                                                               • Environmental pollution

                                                                               Brodell LA, Beck LA, Saini SS. Ann Allergy Asthma Immunol. 100:291-7, 2008

              Factors Which Exacerbate                                                                    Associations
              Chronic Ordinary Urticaria
                                                                            • Angioedema: occurs in 40-80%, mainly
                                                                              affecting the eyelids, lips or tongue. While
 •   Non-steroidal anti-inflammatory drugs (NSAIDS)
                                                                              alarming, it is almost never fatal
 •   Certain “pseudoallergens” in foods
                                                                            • Physical urticarias: (usually symptomatic
 •   Consumption of alcohol                                                   dermatographism or pressure urticaria)
 •   Intercurrent viral infections                                            occur in about 50%
 •   Stress / overtiredness                                                 • Functional thyroid disease: (hypo- or
 •   Exposure to hot environments                                             hyperthyroidism) occurs in about 20%
                                                                              and Hashimoto’s disease in about 15%

                                                                         Leznoff A, Sussman G. J Allergy Clin Immunol 84:66-71, 1989.
                                                                         Greaves M. N Eng J Med 332:1767-1772, 1995.
                                                                         Kaplan A. J Allergy Clin Immunol 114:465-474, 2004.

                 Chronic Ordinary Urticaria                                         Laboratory Investigations in
                  Impacts Quality of Life                                            Chronic Ordinary Urticaria
                                                                          •Patients with chronic urticaria are invariably
 • Using a QOL instrument: the impairment of
   QOL due to chronic urticaria has been shown                             over-investigated
   to be equal in magnitude to that experienced                           •Reasonable investigations include
   by patients with triple coronary artery disease                        • CBC, SMAC, CXR, ESR, CH50
   awaiting bypass surgery                                                • Serology: HCV, HBV, EBV, ANA
 • Chronic urticaria: is also a source of                                 • Thyroid function and thyroid autoantibody
   significant economic cost due to
                                                                            screen (antimicrosomal and antithyroglobulin)
   absenteeism and cost of medications
                                                                          • Poor response to antihistamines: a skin biopsy
O’Donnell BF Br J Dermatol.136:197-201,1997
                                                                            should be performed to exclude urticarial
Poon E, Seed PT, Greaves MW, et. al. Br J Dermatol 140:667-671, 1999.
Baiardini I, Giardini A, Pasquali M, et. al. Allergy 58:621-623, 2003.      vasculitis
 Thyroid Antibodies and Urticaria                                                     Autoimmune Chronic Urticaria
                                                                               • 25-50% of patients with chronic urticaria have
• Prospective study showed anti-thyroid                                          complement activating IgG1 and/or IgG3
  antibodies present in 27% chronic                                              autoantibodies with histamine releasing
  urticaria versus 3.3% healthy controls                                         functional activity against the high affinity IgE
                                                                                 receptor FcεR1 or less commonly against IgE
• Autoimmune thyroid disease may be                                              itself
  associated with euthyroid, hypo- or                                          • These autoantibodies dimerize IgE receptors
  hyper- thyroid functional status                                               expressed on dermal mast cells leading to
• More common in autoimmune chronic                                              complement activation and dermal mast cell
  than idiopathic chronic urticaria                                              activation
                                                                               Niimi N, Francis D, Kermani F, et. al. J Invest Dermatol 106:1001-1006, 1996.
Monge C, Demarco P, Burman KD, et al. Clin Endocrinol 67:473-75, 2007          O’Donnell B, O’Neill C, Francis D, et. al. Br J Dermatol 140:8530858, 1999.
                                                                               Soundararagan S, Kikuchi Y, Joseph K, et. al. J Allergy Clin Immunol 145:815-821, 2005.
                                                                               Kaplan AP, Greaves M. Clin Exp Allergy. 39:777-787, 2009.

 Mast cell activation: Bivalent cross-linking                                         Autoimmune Chronic Urticaria
 of the high affinity IgE receptor by specific
              IgG autoantibody

                   Kaplan AP, Greaves M. Clin Exp Allergy. 39:777-787, 2009.

                                Autoimmune Chronic Urticaria                                    Immune Pathogenesis
                                                                                 1. IgG antibody to IgE receptor cross-links adjacent α
                                                                                    subunits to cause cutaneous mast cell (and basophil)
                                                                                    activation, degranulation and histamine release

                                                                                 2. Predominant IgG antibody subclasses are IgG1 and
                                                                                    IgG3 which are complement fixing

                                                                                 3. Complement activation by two adjacent IgG-Fc
                                                                                    regions (requires 4 IgE receptor α subunits)

                                                                                 4. Release of C5a anaphylatoxin from C5 which
                                                                                    stimulates mast cell to augment histamine release
                                                                                Hide M, Francis D, Grattan C, et. al. N Eng J Med 328:1599-1604, 1993.
                                                                                Kikuchi Y, Kaplan A. J Allergy Clin Immunol 107:1056-1062, 2001.
                                                                                Kikuchi Y, Kaplan A. J Allergy Clin Immunol 109:114-118, 2002.
                                                                                Sabroe RA, Fiebiger E, Francis DM. J Allergy Clin Immunol 110:492-499, 2002.
                                                                                Najib U, Sheikh J. Allergy Asthma Proc. 30:1-10,2009.
                                                                                              Skin biopsy in chronic idiopathic
       Abnormal basophil responsiveness
                                                                                              and chronic autoimmune urticaria
      1. Basophils of patients with chronic urticaria are hyporesponsive to
         polyclonal anti-IgE based on histamine release                                  1.      Non-necrotizing perivascular infiltration

      2. Hyporesponsiveness in at least 50% of patients is due to increased
         cytoplasmic phosphatases such as Src-homology-2 containing inositol
                                                                                         2.      Integrity of vessel wall maintained
         Phosphatases (SHIP); Diminished phosphorylation of key signal
         transduction molecules limits histamine release                                 3.      Predominance of CD4(+) lymphocytes with mixture of
                                                                                                       d       ll No basophils. F
                                                                                                 TH1 and TH2 cells. N b              CD8(+) ll
                                                                                                                            hil Few CD8( ) cells
      3. Hyporesponsiveness of basophils is reversible as patients remit
                                                                                         4.      Variable number of neutrophils and eosinophils – more
      4. Patients’ basophils are paradoxically hyperresponsive to a factor                       prominent in chronic autoimmune urticaria than
         in serum                                                                                chronic idiopathic urticaria

Greaves M, Plammer V, McLaughlan P. et. al. Clin Allergy 4:265-271, 1974.
Kern F and Lichteinstein L. J Clin Invest 57:1369-1377, 1976.                           Elias J, Boss E, Kaplan A. J Allergy Clin Immunol 78:914-918, 1986.
Luquin E, Kaplan A, Ferrer M. Clin Exp Allergy 35:456-460, 2005.                        Ying S, Kikuchi Y, Meng Q, et. al. J Allergy Clin Immunol 109:694-700, 2002.
Vonakis B, Vasagar K, Gibbons J, et. al. J Allergy Clin Immunol 119:441-448, 2007.

         Autoimmune Urticaria Features                                                                    Gender and Urticaria
   • Clinically & histologically identical to and
                                                                                                                                         Male                               Female
     indistinguishable from non–autoimmune
     chronic urticaria                                                                           Physical
                       BUT                                                                                                                40%                                60%
     Tends t                        i
   • T d to run a more aggressive and oftend ft                                                Ordinary
     treatment-resistant course                                                                 Chronic                                   30%                                70%
                       AND                                                                      Urticaria
   • More often + for thyroid autoantibodies
                                                                                                Chronic                                   15%                                85%
  Sabroe R, Poon E, Orchard G, et. al. J Allergy Clin Immunol 103:484-493, 1999.
  Najib U, Sheikh J. Allergy Asthma Proc. 30:1-10,2009.
                                                                                         Irinyi B, Széles G, Gyimesi E, et al. Int Arch Allergy Immunol 144:217-225, 2007

     Diagnosis: Autoimmune Chronic Urticaria                                                   Autologous Serum Skin Test
      • Autoimmune urticaria should be suspected if the                                 • H1 antihistamine treatment should be withdrawn at least
        response to regular antihistamine treatment is poor                               48h prior to the test (2 weeks for systemic steroids)
      • Demonstration of serum thyroid antibodies is highly                             • Serum is obtained from the patient during a period of
        suggestive of autoimmune urticaria                                                disease activity, and 0.05ml is injected intradermally into
                                                                                          the forearm skin on both sides. Similar control injections
      • An autologous serum skin test is helpful - a negative
                                                                                          of saline and histamine (10μg/mL-1) are performed
        result effectively rules out autoimmune urticaria, but a
        positive result requires confirmation by in-vitro testing
                                                   in vitro                                 p
                                                                                        • A positive result, read at 30 min, is a red wheal at the
                                                                                          serum site of diameter >1.5mm greater than the saline
      • In-vitro testing consists of demonstrating the ability of
                                                                                          wheal, if present
        the patient’s serum to activate donor basophils* or cells                                                                                                             serum
        of a rat basophil leukemia cell line by release of
        pharmacologic mediators such as histamine
      • Commercial availability detection of serum                                                                                                                             saline
        autoantibodies* v. IgE receptors or v. IgE                                   Grattan CE, Wallington T, Warin R, et. al. Br J Dermatol 114:583-590, 1986.
                                                                                     Grattan CE, Boon A, Eady R, et. al. Int Arch Allergy Immunol 93:198-204, 1990.
      * These tests now commercially available                                       Sabroe RA, Grattan CE, Francis DM. Br J Dermatol 140:446-452, 1999
                 Autologous Serum Test
            for Autoimmune Chronic Urticaria                                                    Management of Chronic Urticaria

                                                                                                   Avoidance of factors known to worsen hives
                                                            Histamine                          •   NSAIDS, opiates, alcohol, spicy foods
                                                                                               •   Overtiredness and stress
                                                            S li                               •   Wearing of tightly fitting garments, footwear
                                                                                               •   Strenuous physical exercise
                                                                                               •   Overheated ambient temperature

                                                                                                              Morgan M. Khan DA. Ann Allergy Asthma Immunol. 100:517-26, 2008.
                                                                                                                           Fromer L. South Med J. 101:186-92, 2008.
Kaplan and Greaves, Clin Exp Allergy. 39:777-87, 2009

   Management of Chronic Urticaria                                                             Management of Chronic Urticaria
             • H1 receptor antagonists
                                                                                                         • H1 receptor antagonists
             • H2 receptor antagonists
                                                                                                         • H2 receptor antagonists
               Leukotriene antagonists
             • L k ti        t    i t
                                                                                                         • Leukotriene antagonists
             • Alternate-day corticosteroids
                                                                                                         • Alternate-day corticosteroids
             • Cyclosporine-A, MTX, others
                                                                                                         • Cyclosporine-A
                  Morgan M. Khan DA. Ann Allergy Asthma Immunol. 100:517-26, 2008.
                               Fromer L. South Med J. 101:186-92, 2008.

   Management of Chronic Urticaria                                                                        Antihistamines Compared
                                                                                                    Generic                       Brand ®                 Drowsy? Dry mouth?
   • Antihistamine treatment                                                                    Diphenhydramine                  Benadryl                      +++               +++
       1. Low sedation (2nd generation) antihistamines first line Rx                            Chlorpheniramine            Chlor-Trimeton                      ++               +++
       2. Taken regularly - not on an “as required” basis                                       Brompheniramine                  Dimetapp                       ++               +++
       3. Loratadine 10mg daily Desloratadine 5mg daily
           Cetirizine 10mg daily Levocetirizine 5mg daily                                           Clemastine                      Tavist                     +++               +++
                           120 180mg
           Fexofenadine 120-180mg daily (adult doses)                                              Hydroxyzine                     At
                                                                                                                                   Atarax                     ++++               ++
       4. Sedative antihistamine (Hydroxyzine 25mg) taken
                                                                                                    Loratadine                     Claritin                  0 to +               0
          before sleep if nocturnal pruritus is a problem; Warn
          about impairment of cognitive function following AM
                                                                                                   Desloratadine                  Clarinex                   0 to +               0
                                                                                                     Cetirizine                    Zyrtec                    Slight               0
   Finn AJ, Kaplan A, Fretwell R. J Allergy Clin Immunol 103:1071-1078, 1999.
   Nelson H, Reynolds R, Mason J. Annals Allergy Asthma Immunol 84:517-522, 2000.                  Levocetirizine                   Xyzal                    0 to +               0
   LaRosa M, Leonardi S, Marchese G, et. al. Annals Allergy Asthma Immunol 87:48-53, 2001.
   Clough B, Boutsiouki P, Church M. Allergy 56:985-988, 2001.
   Verster J, Volkerts E, van Oosterwijck et. al. J Allergy Clin Immunol 111:623-627, 2003.
                                                                                                   Fexofenadine                    Allegra                       0                0
   Verster J, Volkerts E Annals Allergy Asthma Immunol 92:294-303, 2004.
   Klimek L. Drugs Today. 45:213-245, 2009                                                    Adapted from: Shamsi Z, Hindmarch I. Hum Psychopharmacol 15(S1):S3-20, 2000
       ? Advantage Levocetirizine                                                       Management of Chronic Urticaria
                                                                                        • In resistant cases, off-label (HIGH)
• Highest affinity to H1 receptors of all                                                 doses of low sedation antihistamines
  non-sedating antihistamines                                                             (360mg fexofenadine daily) are effective
• High bioavailability and slow metabolism                                                and safe Zuberbier T, Maurer M. Acta Derm Venereol. 87:196-205, 2007.
• C
  Consistently rapid therapeutic onset
       i t tl       id th      ti      t                                                • H2 antihistamines: doubtful efficacy as
  with high efficacy rate; good tolerability                                              monotherapy, but are useful in patients
     (minimal to no sedation)                                                             with a history of corticosteroid toxicity
                                                                                            Linn J. Ann Emergency Med. 36:462-68, 2000.

                                                                                        • Note: only 15% of cutaneous histamine
                                                                                          receptors are of the H2 variety!
Dubuske LM. Allergy Asthma Proc. 28:724-34, 2007.                                       • EG: Combine ranitidine with an H1 blocker
Ducharme EE, Weinberg J. J Drugs Dermatol. 8:243-7, 2009.

    What If Antihistamines Don’t Work?                                                   What If Antihistamines Don’t Work?
  • Add montelukast 10mg daily: It helps some                                           • Cyclosporine: best known for its
    but not all patients; adverse effects rarely a                                        effectiveness in autoimmune urticaria, is also
    problem                                                                               effective in non–autoimmune chronic
                                                                                          urticaria. Dosage 4-6mg/kg/day, with regular
  • Add doxepin 10-25mg at night: tricyclic is                                            checks of renal function and blood pressure.
    a very potent H1 and H2 antihistamine, but                                            It is especially valuable in patients with
    causes significant sedation. It should not                                              h    i t     id t i it
                                                                                          chronic steroid toxicity
    be given with antidepressants                                                       • Intolerance or ineffectiveness of
  • Prednisone: short tapering courses starting                                           cyclosporine: methotrexate 10-25mg orally
    at 30-40mg daily are useful to deal with the                                          once weekly, or mycophenolate mofetil 1-2g
    occasional temporary flare-up; Rapid taper!                                           daily tried; anti-IgE monoclonal antibody?
 Goldsobel AB, Rohr AS, Siegel SC, et al. J Allergy Clin Immunol. 78:867-73, 1986.     Grattan CE, O’DonnellBF, Francis DM. Br J Dermatol. 143:365-72, 2000 (Cyc-A)
 Kaplan A. N Eng J Med 346:175-179, 2002.                                              Shahar E, Bergman R, Guttman-Yassky E, et al. Int J Dermatol. 45:1224-7, 2006 (Mycofenolate)
 Kozel MM, Sabroe RA. Drugs. 64:2515-2536, 2004.                                       Ben-Shoshan M. Recent Pat Inflamm Allergy Drug Discov. 2:191-201, 2008. (Anti-IgE)
 Khan DA. Allergy Asthma Proc. 29:439-46, 2008.                                        Kaplan A. N Eng J Med 346:175-179, 2002 and J Allergy Clin Immunol. 123:713-7, 2009. (Cyc-A)

                     Antihistamines                                                     Sedation with Antihistamines
                H1 receptor antagonists
                                                                                      • Clearly more evident with first generation
                                         Properties                                     antihistamines and more likely to adversely
1. Bind to H1 receptors on endothelial cells and                                        affect performance
   induce an inactive conformation. Histamine
   binds to the same receptors and induces an
                                                                                        Second and third generation antihistaminics
                                                                                      • S       d d thi d         ti     tihi t i i
   active conformation
                                                                                        are more specific for H1 receptor, are less
2. Efficacy is proportional to receptor occupancy                                       likely to cross the blood-brain barrier, and can
   i.e., histamine vs. antihistamine, varies with                                       be effective from 12-24 hrs
   dose, half-life, distribution in the skin, and
   receptor affinity                                                                 Simons F, Fraser T, Reggin et. al. Clin Exp Allergy 26:1092-1097, 1996.
                                                                                     Weiler J, Bloomfield J, Woodwarth G, et. al. Ann Int Med 132:354-363, 2000.
                                                                                     Verster J, Volkerts E, van Oosterwijck et. al. J Allergy Clin Immunol 111:623-627, 2003.
                                                                                     Verster J, Volkerts E Annals Allergy Asthma Immunol 92:294-303, 2004.
 Simons F. N Eng J Med 351:2203-2217, 2004.
       Sedation with Antihistaminics                                                                                                 Cyclosporine
                  (cont.)                                                                         • Effective in chronic autoimmune urticaria with
                                                                                                    success rate of 75%
                                                                                                  • Effectiveness demonstrated with two double-
  • Receptor occupancy may be greater with
                                                                                                    blind placebo controlled studies
    high dose first generation antihistamines
    given q.i.d. for severe symptoms compared                                                     • Effectiveness in chronic idiopathic urticaria
    to current recommended doses of second                                                          (1 RCT) and pressure urticaria (anecdotal)
    and third generation antihistamines                                                           • Is steroid-sparing
  • No sedation or performance studies have                                                       • Requires monitoring blood pressure, BUN,
    ever been done in patients with chronic
                                                                                                    creatinine, and urinalysis every 6 weeks.
    urticaria - studies are short term using
    normal volunteers or pt with allergic rhinitis                                                • Typical effective dose (adults) 200-300 mg/day
Schweitzer P, Muehlbach M, Walsh J . J Allergy Clin. Immunol 94:716-724, 1994.
Bender B, Berning S, Dudden R, et. al. J Allergy Clin Immunol 111:770-776, 2003.                  Toubi E, Blant A, Kessel A. Allergy 52:312-316, 1997.
Verster J, de Weert P, Bijtjes S, et. al. Psychopharmacol 169:84-90, 2003.                        Grattan C, O’Donnell B, Francis D, et. al. Br J Dermatol 143:365-372, 2000.
                                                                                                  Vena GA, Cassano N, Colombo D, et al. J Am Acad Dermatol. 55:705-9, 2006.

                                                                                                  Treatment of Autoimmune Chronic Urticaria
                                                                                                   • The options for treatment include all the therapies
                                                                                                     mentioned for non–autoimmune patients
                                                                                                   • Many patients require off-label (high) dosages of
                                                                                                     the various H1 antihistamines
                                                                                                   • Cyclosporine is reputed to be more effective in
                                                                                                     autoimmune than non autoimmune chronic urticaria
                                                                                                   • IVIg and plasmapheresis have proven highly effective
                                                                                                     in selected refractory cases
                                                                                                   • Anti-IgE monoclonal antibody (omalizumab) may
                                                                                                     benefit both types of chronic urticaria

                                                                                                  Grattan CE, Francis DM, Slater NGP, et. al. Lancet 339:1078-1080, 1992.
                                                                                                  O’Donnell BF, Farr RM, Kobza-Black A, et. al. Br J Dermatol 138:101-106, 1998.
      Grattan C, O’Donnell B, Francis D, et. al. Br J Dermatol 143:365-372, 2000.                 Kaplan A, Joseph K, Maykut R, et. al. J Allergy Clin Immunol 122:569-573, 2008.

         Therapeutic Efficacy Compared                                                                                 Urticarial Vasculitis?
                                                                                                    • Individual wheals persist for more than 24h
                            Antihistamines                   Steroids              Cyclosporine
                                                                                                    • Wheals resolve but leave residual staining
  Physical Urticaria
                                                                                                    • Itching is inconsistent, but wheals may be
  Dermatographism                   70-77%                       N/D                   N/D            tender and painful
      Ch li     i
                                                                                                        y         y p               g
                                                                                                    • Systemic symptoms including arthralgiag
      Urticaria                        77%                       N/D                   N/D          • Minority: hypocomplementemia
 Chronic Idiopathic                                                                                 • Poor response to antihistamine treatment
    Urticaria                          68%                       64%                   36%
                                                                                                    • Morphology of urticarial eruption may
  Autoimmune                                                                                          include purpura at inner edge of annular
  Chronic Urticaria                    13%                       54%                   79%            lesion

Irinyi B, Széles G, Gyimesi E, et al. Int Arch Allergy Immunol 144:217-225, 2007                           Brown NA, Carter JD. Urticarial vasculitis (Review) Curr Rheumatol Rep. 9:312-9, 2007.
                     Urticarial Vasculitis

Urticarial Vasculitis: Associations                                       Urticarial Vasculitis: Diagnosis
                                                                        • Hypocomplementemia: is occasionally
  • Urticarial vasculitis may be a sign of….                            found, and is usually associated with
                                                                        systemic involvement (arthritis, pulmonary
  • Autoimmune connective tissue diseases
    (Sjogren’s syndrome, SLE, RA)                                       hypertension)
                                                                        • Diagnosis is dependent on histological
  • Viral hepatitis (HBV, HCV)
                                                                          features of leukocytoclastic vasculitis
  • Paraproteinemia
                                                                                   Endothelial swelling of post–capillary venules
  • Inflammatory bowel disease                                                     Red cell diapedesis
                                                                                   Fibrin deposition
                                                                                   Leukocytoclasis: either lymphocytes OR neutrophils
Agnello V, Koffler D, Eisenberg J. J Exp Med 134:2285-2415, 1971.                  Direct immunofluorescence usually unhelpful
McDuffie F, Sams JW, Maldonado J. Mayo Clin Proc 48:340-348, 1973.
Black AK. Clin Dermatol 17:565-569, 1999.
Venzor J. Clin Rev Allergy Immunol 23:201-216, 2002                    Soter N, Mihm MJ, Gigli, et. al. J Invest Dermatol 66:344-350, 1976.
                                                                       Lee JS, Loh TH, Seow SC, et al. J Am Acad Dermatol. 56:994-1005, 2007.

Histology: Chronic Urticaria v. Urticarial Vasculitis

                                                                     The photomicrograph shows endothelial cell swelling, perivascular fibrin
                                                                      deposition, neutrophil perivascular infiltration, neutrophil granulocyte
                                                                        fragmentation (leukocytoclasia) and the presence of nuclear dust
                        Urticarial Vasculitis                                           Urticarial Vasculitis Treatment
                      Laboratory Investigation
                                                                                    • Antihistamines are usually ineffective
          •    Complement screen
                                                                                    •    Dapsone (screen for G6-PD deficiency)
          •    ESR, CRP
                                                                                    •    Colchicine
          •    Viral screen (hepatitis A, B, C)
                                                                                    •    Hydroxychloroquine
          •    Serum protein electrophoresis (SPEP)
                                                                                    •    P d i
                                                                                         Prednisone ( i        ih        i i    l      )
                                                                                                    (patients with systemic involvement)
          •    ANA, rheumatoid factor, anti-Ro/La
                                                                                    •    Intravenous immunoglobulin
          •    Stool occult blood (IBD)
                                                                                    •    Plasmapheresis
          •    Chest X ray, ECG, Echocardiogram
                                                                                Lopez LR, Davis KC, Kohler PF, et. al. J Allergy Clin Immunol 73:600-603, 1984.
                                                                                Abookaker J, Greaves MW. Clin Exp Dermatol 11:436-444, 1986.
                                                                                Mehregan DR, Hall MJ, Gibson LE. J Am Acad Dermatol 26:441-448, 1992.
   Davis MDP, Daoud MS, Kirby B, et. al. J Am Acad Dermatol 38:899-905, 1998.
                                                                                Athanasiadis GI, Pfab F, Kollman A. Allergy 61:1484-1485, 2006.
                                                                                Chang S, Carr W. Allergy Asthma Proc. 28:97-100, 2007.

                  Chronic Urticaria + Fever                                                        Schnitzler’s syndrome
                                                                                  This is the association of often non-pruritic but
                                                                                  otherwise unremarkable chronic urticaria with IgM
          1. Schnitzler’s syndrome (bone pain,                                    (rarely IgG) kappa gammopathy on serum protein
             paraproteinemia, B-cell lymphoma)                                    electrophoresis AND…..
                                                                                  • Fever and Bone pain
          2. Muckle-Wells (urticaria, amyloidosis
             and deafness)                                                        • Urticarial vasculitis on skin biopsy
                                                                                  • Poor response to antihistamines
          3. FCAS (Familial cold autoinflammatory
                                                                                  • Good response to interleukin-1 receptor antagonist
          4. NOMID (neonatal onset mutisystem
                                                                                  • Effective?: cyclosporine, rituximab. MTX
             inflammatory disorder)
                                                                                  • Occasional progression to B cell lymphoma

                                                                                  Berdy SS, Bloch KJ. J Allergy Clin Immunol 87:849-854, 1991.
                                                                                  deKoning HD, Bodar EJ, Van derMeer JW, et. al. Seminars Arthritis Rheum 37:137-148, 2007.
              Note: # 2, 3 and 4 above are present at or near birth               Eiling E, Moller M, Kreiselmaier, et al. J Amer Acad Dermatol. 57: 361-4, 2007.
                                                                                  Wastiaux H. Barbarot S, Gagey-Caron V, et al. J Eur Acad Dermatol Venereol 23:85-87, 2009.

       Autoinflammatory syndromes: CAPS                                             Autoinflammatory syndromes: CAPS
         (cryopyrin – associated periodic                                             (cryopyrin – associated periodic
                   syndromes)                                                                syndromes) (cont.)
   • CAPS: presents as persistent urticaria from birth,
     often worse in the evenings, with minimal or no                            • NOMID (neonatal onset multisystem inflammatory
     pruritus, fever and arthralgia; all are associated with                      disorder) is more severe, with sensorineural
                                                                                  deafness, other CNS abnormalities (chronic
     mutation in the CIAS1 gene leading to cryopyrins                             recurrent sterile meningitis) and arthropathy
     (fever-inducing proteins)
     (f     i d i        t i )
   • FCAS: (familial cold autoinflammatory syndrome) represents                 • All three syndromes seem to respond well to
     the mildest form with atypical cold urticaria and febrile episodes           anakinra (recombinant IL-1 receptor antagonist)
   • Muckle-Wells syndrome: presents with chronic urticaria and
     senorineural deafness from birth, with fever; arthralgia and
     renal amyloidosis may develop in adult life

                                                                                Hoffman HM, Muellar JL, Broide DH, et. al. Nature Genetics 29:301-305, 2001.
Hoffman HM, Muellar JL, Broide DH, et. al. Nature Genetics 29:301-305, 2001.    Aganna E, Martinon F, Hawkins RN, et. al. Arthritis Rheum 46:2445-2452, 2002.
Aganna E, Martinon F, Hawkins RN, et. al. Arthritis Rheum 46:2445-2452, 2002.
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