Potential Causes of Chronic Urticaria

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Chronic Urticaria
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Mast Cell
Before Resting Cell
After Activated Cell
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Allergen-IgE dependent Mast Cell Activation
Signal Transduction Pathways
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Mast Cell Activation
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Mast cell mediators
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CU-histology
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Lesional T cells in CU the
presence of activated T cells in the dermis may
play a role in the pathogenesis of the skin
lesions in CU.Mekori YA et al. J Allergy Clin
Immunol 72681, 1983 Our results suggest that
the infiltrate resembles that observed in
cellular immune reactions (although no antigen
has been identified) and that interaction of
T-lymphocytes and/or monocytes with mast cells to
cause mediator release appears likely.Elias J
et al. J Allergy Clin Immunol 78914, 1986
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A Novel Mast Cell Activation Pathway
contact
Activation of Mast Cells Degranulation Release
of TNF-a
Activated T Cells J. Immunol 1604026,
1998 J. Leukoc. Biol. 63337, 1998
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Mast Cells Release Histamine Following Coculture
with Anti CD3-Activated T Cells
Histamine Release ()
BMMC alone
anti CD5
anti CD3
N.T.
T cells incubated on wells coated with
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Kinetics of T Cell-Induced Histamine Release and
Aggregate Formation
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Histamine Release ( of total)
Aggregation
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10
0
20
BMMC alone
0
10
0
20
10
Time (hours)
Time (hours)
2B4 N.T.
2B4 N.T.
2B4 IgG
2B4 IgG
2B4 anti CD3
2B4 anti CD3
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Induction of Degranulation is Inhibited by
Separation of T Cells and Mast Cells
Histamine Release ( of total)
Normal
Transwell
N.T.
IgG
anti CD3
2B4 cells incubated on wells coated with
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Increased p21Ras Expression in PBMC of Patients
with CU
Confino et al. JACI Jan. 200l
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Aberrant Regulation of p21 Ras in CU possible
pathogenic mechanisms
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Anti FceRI/IgE
0.05 ml autologous serum i.d. to uninvolved
skin result wheal 1.5mmgtcontrol (NaCl) at 30
min. ( 80 sens. /spec.)
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FceRI
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Positive Autologous Serum Test
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CU sera-inducing degranulation
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Effect of C5 on Degranulation
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Points in Favour of Pathogenic Ab in CIU

• Passive transfer of autologous ST to healthy
  volunteers
• (Adv Dermatol 15311, 1999)
• Correlation of functional autoAb plasma levels
  with severity (Lancet 3391078, 1992)
• Disease remission following removal
  (plasmapheresis) or suppression (IVIG) of the
  antibody (BJD 138101,1998)

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Prevalence of Autoantibodies in 78 Patients with
CU Sabroe
RA Greaves MW BJD 154813, 2006
(IgG1 , IgG3)
(IgG2, IgG4)
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Thyroid Autoimmunity in Chronic Urticaria27 of
patients with CU have anti thyroid Ab. 19 have
abnormal thyroid functionKaplan AP N Eng J Med
346175, 200224 of patients with CIU had at
least one type of anti thyroid Ab. 42 of the
seropositive pt. had thyroid disease or altered
TSH levels. Zauli D et al Allergy Asthma Proc
2293, 2001 10 euthyroid patients with CU.
7/10 had anti thyroid Ab. All seven reported
resolution of symptoms within 4 wk of thyroxine
treatment. Other 3 patients did not respond. 5
patients had a recurrence of symptoms after
treatment was stopped, which resolved after
treatment was restarted.TSH decreased in all pt.
With a clinical response.Rumbyrt JS et al J
Allergy Clin Immunol 96901, 1996
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Thyroid Autoimmunity in Chronic Urticaria

• 182 Patients

90 AST 92 AST-
18 TMA
4 TMA
RR for TMA positivity 4.06 (CI 1.6-10.6)
13 1 TSH out of
the normal range
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Clinical and laboratory parameters in predicting
chronic urticaria duration a prospective study
of 139 patients

• 139 patients with CU
• 70 gt 1 year
• 14gt 5 years
• CU duration is associated with clinical
  parameters such as
• severity and angioedema
• autologous serum test and anti-thyroid antibodies

Toubi E et al Allergy 59869, 2004
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Potential Causes of Chronic Urticaria

• Occupational/Contactants
• Medications
• Foods/additives/CAM products (Echinacea Ann
  Allergy 8842, 2002)
• Physical
• Infections (viral focal)
• Autoimmune (SLE MCTD thyroiditis aFceRI)
• Vasculitis (less than 1)
• Hormonal dysfunctiuon (thyroid pregnancy
  menstrual)
• Malignancy
• Mastocytosis

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Dermographism
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Cold Urticaria
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Delayed Pressure Urticaria
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Cholinergic Urticaria
Eleven of 17 patients with cholinergic urticaria
showed positive reactions in skin tests with
their own diluted sweat. Substantial amounts of
sweat-induced histamine release from autologous
basophils were observed in 10 of 17 patients.
Eight of 15 patients with cholinergic urticaria
showed positive reactions in the autologous serum
skin tests. All 6 patients who developed
satellite wheals after the acetylcholine test
showed hypersensitivity to sweat. Further,
patients whose eruptions were coincident with
hair follicles showed positive responses to the
skin test with autologous serum, whereas patients
whose eruptions were not coincident with hair
follicles did not.
Eleven of 17 patients with cholinergic urticaria
showed positive reactions in skin tests with
their own diluted sweat.
Fukunaga A et al J allergy Clin Immunol 116 397,
2005
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H. Pylori Infection in Chronic Urticaria H.
pylori was diagnosed in 17 of 25 pt. with CU. GI
symptoms were present in 10 of the 17. After
treatment, 8/17-complete remission, 6/17 partial
remission (in all Hp test became negative). In
the 3 non-responders H.pylori was still
detectable.
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CU-Exacerbating Factors

• Viral Infection
• NSAID
• Alcohol
• Overheating

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Treatment of CU
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Suggestive Therapeutic approach for CU Patients
with AutoAb
BJD 154813, 2006
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CU-Experimental Therapies

• Cyclosporine (2.5-4 mg/kg) Tacrolimus (70
  response rate)
• Plasmapheresis (pts. with aFceRI Ab)
• IVIG
• Levothyroxine (for pts. with athyroid Ab)
• Anti IgE mAb (effect on FceRI expression)