The study evaluated 195 patients with chronic idiopathic urticaria to determine the correlation between biomarkers of autoimmunity like ANA, ATA, and disease severity. It found that 46% of refractory patients tested positive for the CU Index compared to 30% of controlled patients. Combinations of biomarkers had slightly better sensitivity and negative predictive value than individual biomarkers for identifying refractory cases. The CU Index alone had the best specificity and positive predictive value.

1. (J Allergy Clin Immunol 2012;129:1307-13)
Sadudee (Boonmee) Klakayan, MD

2. Introduction
• Chronic urticaria (CU) : recurrent urticarial lesion
for more than 6 week with symptoms present at
least 3 times weekly
• When the cause is not detected after intensive
clinical and laboratory investigation, it is defined
as idiopathic
• autoimmune mechanisms have been proposed as
responsible for the development of some of the
cases of chronic idiopathic urticaria (CIU)
(J Allergy Clin Immunol 2012;129:1307-13)

3. Physical urticaria Chronic urticaria
- Cold urticaria
- Cholinergic urticaria
- Dermographism
- Pressure urticaria
- Solar urticaria Autoimmune chronic Chronic idiopathic
-Aquagenic urticaria urticaria urticaria
45% 55%
Urticarial vasculitis
IgG antiFcεRIα IgG antiIgE
subunit
5-10%
35-40%

4. • Thyroid disease is the most frequently
investigated disease in association with CIU
• Arthur Leznoff et al.
- 17 of 140 cases (12.1%) of chronic urticaria, demonstrated thyroid
autoimmunity with thyroid microsomal antibodies (TMAs)
≥ 1: 1600
- 8 of 17 pt. had goiter or thyroid dysfunction
- age and sex and thyroid features were similar to pt.with
autoimmune thyroiditis
- CUA may have an autoimmune basis
(Arch Dermatol 1983;119:636-640)

5. Are autoantibodies present in patient with
subacute and chronic urticaria ?
• Survey of autoantibodies in patients with
idiopathic subacute and chronic urticaria
• 25 pt. vs 75 control (serum tested for
autoantibodies)
• age 15 to 73 years (mean 48 yr)
J Investig Allergol Clin Immunol. 2001;11(1):16-20

6. • 1 pt. inflammatory bowel disease
1 pt. multiple myeloma
otherwise no other diagnoses of disease
specifically involving immunity other than
atopy
• No study patients had diagnosis of
autoimmune thyroid disease
J Investig Allergol Clin Immunol. 2001;11(1):16-20

7. • Antibodies to thyroid peroxidase (TPO)
common in urticaria 20% vs controls 0%
(p < 0.01)
• Rheumatoid factor(RF) increased in urticaria
16% vs controls 0% (p < 0.05)
• Neither H. pylori antibody nor other
autoantibodies were present in significant
numbers of urticaria patients compared to
controls.
J Investig Allergol Clin Immunol. 2001;11(1):16-20

8. • Conclusion : pt. with urticaria more likely to
have a thyroid autoantibody to TPO or to have
RF
• This survey demonstrates that some markers
of autoimmunity (TPO and RF)may be
increased in urticaria patients, but other
markers of autoimmunity were not found
J Investig Allergol Clin Immunol. 2001;11(1):16-20

9. (J Allergy Clin Immunol 2012;129:1307-13)

10. Objective
• Aimed to characterize the association
between CU, autoimmune diseases, and
autoimmune/inflammatory serologic markers
in a large unselected population
(J Allergy Clin Immunol 2012;129:1307-13)

11. Methods
• Maccabi Healthcare Services (MHS) in Israel
• Using an automated search on the MHS central
database
• Collected data on all pt. diagnosis of CU by either
allergist and clinical immunology or dermatologist
between January 1, 1993, and March 1, 2010 using
the ICD-9-CM
(J Allergy Clin Immunol 2012;129:1307-13)

12. • Excluded : physical urticaria, cholinergic urticaria,
dermographism, and urticaria without
specification of ‘‘chronic’’ have distinct ICD-9-CM
• control subjects  pt. who visited
- dermatologists
- family physicians
- allergist
not given diagnosis of CU or any other specific
disease but were given diagnoses with the ICD-9-
CM “ Patient under observation ”
• Control subjects matched with cases by age and
sex
(J Allergy Clin Immunol 2012;129:1307-13)

13. • For each patient, collected information on
diagnostic history of
- hypothyroidism, hyperthyroidism,
- systemic lupus erythematosus (SLE)
- rheumatoid arthritis (RA)
- celiac disease
- type 1 diabetes mellitus
- Sjögren syndrome
• The first registration date for each diagnosis
was collected
(J Allergy Clin Immunol 2012;129:1307-13)

14. • Laboratory tests :
- antithyroid peroxidase antibodies
- antithyroglobulin antibodies
- antinuclear antibodies
- rheumatoid factor
- anti–dsDNA antibodies
- anticardiolipin antibodies
- anti–transglutaminase IgA antibodies
- anti–parietal cell antibodies
- mean platelet volume (MPV)
• Studies for antibodies to FcεRI or IgE were not available in
Israel for routine clinical work
• Each patient, calculated the number of laboratory tests
performed and the proportion of abnormal test results
(J Allergy Clin Immunol 2012;129:1307-13)

15. RESULTS

16. Study group Control group
Diagnoses of Control
CU =12,778 pt =10,714 pt.
Women = men = 4,306 women = men = 1,526
8,472 (66.3%) (33.6%) 9,188 (85.7%) (14.3%)
Average age 45.3 +/- 18.5 years Average age 44.2 +/- 14.2 years
(J Allergy Clin Immunol 2012;129:1307-13)

17. Thyroid disease and CU

18. (J Allergy Clin Immunol 2012;129:1307-13)

19. With in 10 yr
(J Allergy Clin Immunol 2012;129:1307-13)

21. Other autoimmune disease and CU

22. (J Allergy Clin Immunol 2012;129:1307-13)

23. With in 10 yr
(J Allergy Clin Immunol 2012;129:1307-13)

25. • few autoimmune diseases were diagnosed during the first 6 months
after the diagnosis of CU
• most continuously revealed over more than 10 years
• suggest that accompanying autoimmune diseases were independently
diagnosed and not as part of the CU workup

26. • OR of pt with CU with additional autoimmune
disease = 17.343 compared with control
(95% CI, 14.222-21.148; P < .0005)
• 1,872 pt with CU with autoimmune diseases
- 12.5% (n =1591)  1 autoimmune disease
- 2.1% (n = 263)  2 autoimmune diseases
(hypothyroidism and another, mostly RA)
- 0.1% (n= 16)  3 autoimmune diseases
- 1 pt. 4 autoimmune diseases
- 1 pt. 5 autoimmune diseases
(J Allergy Clin Immunol 2012;129:1307-13)

27. Serologic and Labortory markers and CU

28. Abnormal high
306 CU pt.with hypothyroidism have Antithyroid Ab( ATG,ATPO)
(J Allergy Clin Immunol 2012;129:1307-13)

29. • Pt. CU group 11,514 pt. with euthyroid
Lab CU patient Control OR P value
With
euthyroid
ATPO Ab 312 6 24.24 < 0.0001
ATG 74 1 17.37 <0.0001
(J Allergy Clin Immunol 2012;129:1307-13)

30. Discussion
• This study is the first large control study
demonstrating a correlation between CU and
the main autoimmune diseases and serologic
markers
• women affected twice as often as men

31. • Thyroid disease were most common autoimmune
disease accopanying pt with CU
from this study Pt with CU Dx
- hypothyroidism = 10%
- hypertrhyroidism = 2.6%
signinicant than control and normal population
group
• Antithyroid peroxidase and antithyroglobulin more
significant prevalent in Pt. with CU than control
group and physician were also diagnosed thyroid
disease

32. • Aversano et al hypothesized that inflamatory
status induced by thyroid- stimulating hormone
led to flares of urticaria and production of
antithyroid antibodies
• The author suggest that the association between
CU and thyroid disease might due to share
susceptability to autoimmune or chronic
inflammatory process ( finding of other
autoimmune disease were more common in CU
pt.)

33. • Rheumatoid arthrits second most common
autoimmune disease in pt. with CU
- 1.9% of female pt. with CU (significant more
prevalent than control group and normal
population)
- Rheumatoid factor +ve often in female and male
pt. with CU than control
• Type I DM, Sjögren syndrome, celiac disease and SLE
significant more prevalent in female pt. with CU than
control

34. • Strengths of this study
- large population of pt. with CU
- compared with large match control group
- retrospective study : correlation of CU and
autoimmunity and proinflammatory marker
• Limitation of study
- retrospective study : to evaluate
autoimmune diasease and serologic marker
that have effect or relation to CU required
detail information and closed follow up

35. Conclusion
• Clinical implications:
- CU is probably one of the autoimmune
diseases
- Understanding the disease process might
help the development of individualized
therapies and increase awareness of
comorbidities, as well as help in the prediction
of disease prognosis

37. • Over the past 2 decades, studies have suggested an
autoimmune mechanism underlying the pathophysiology of
CIU in up to 50% of the patients
• Clinicians have also observed an association between CIU and
thyroid antibodies in approximately 15 to 25% of CIU patients
• purpose of study
- to determine correlation of biomarkers for autoimmunity
(ANA or ATA, either individually or in combination with the CU
Index) and disease severity in CIU
• CU index : commercial basophil histamine release assays to
screen for a functional autoantibody to FcεRI
Ann Allergy Asthma Immunol 108 (2012) 337–341

38. Methods
• Retrospective analysis patients with an ICD-9 diagnosis
of chronic idiopathic urticaria from October 1, 2007
through September 30, 2009
in allergy clinic at tertiary care in Wisconsin
• 195 pt. (age ≥ 18) were included
• Exclusion : if they had primarily physical or cholinergic
urticaria, acute urticaria, food or drug-related urticaria,
vasculitis, mastocytosis, or exclusively angioedema
without evidence of urticaria.
Ann Allergy Asthma Immunol 108 (2012) 337–341

39. • Classified into 2 groups: they
- Controlled if they required only H1/H2
antihistamines with or without a leukotriene
receptor antagonist (LTRA) for control of their
hives
- Refractory if they continued to have physical
evidence of urticaria on this regimen
Ann Allergy Asthma Immunol 108 (2012) 337–341

40. • Laboratory data
- ANA
- anti-thyroperoxidase antibody (ATPO)
- anti-thyroglobulin antibody (ATG)
- CU Index (basophil histamine release assay)
• positive result were
- CU Index (>10)
- ANA (titer > 1:160)
Ann Allergy Asthma Immunol 108 (2012) 337–341

41. Results
• Demographic data
• All four biomarkers (CU Index, ANA, ATG, ATPO) were measured in 25% of
CIU patients
• at least 1 biomarker was measured in 84% of patients
• No autoimmune biomarker was measured in 32 (16%) CIU patients
Ann Allergy Asthma Immunol 108 (2012) 337–341

42. Results
• Percentage of patients with positive autoimmune
biomarkers
Ann Allergy Asthma Immunol 108 (2012) 337–341

43. Results
• Autoimmune biomarkers and disease severity
80%
46%
50%
30%
Ann Allergy Asthma Immunol 108 (2012) 337–341

44. Results
• Test characteristics of combinations of autoimmune
biomarkers
4.5
2.3
3.1
Ann Allergy Asthma Immunol 108 (2012) 337–341

45. Results Sensitivity, specity,PPV,NPV for identify a
refractory outcome in CIU
• CU Index has
superior SPEC and
PPV for identifying a
refractory outcome
in CIU
• combinations of
ANA and anti-thyroid
antibodies
slightly better SENS
and NPV
Ann Allergy Asthma Immunol 108 (2012) 337–341

46. • Cost of order the autoimmune biomarkers
- ANA= $84.20
- ATG = $128.00
- ATPO= $118.00
- CU Index = $436.00
- combination of the ANA, ATG, and ATPO = $330.20
• Need for establishing screening tools to identify pt.
who are likely to remain refractory to conventional
therapy and allow for an optimal and appropriate
management in a timely and cost-effective manner
Ann Allergy Asthma Immunol 108 (2012) 337–341

48. Mediator of hives and swelling
Mast cell (cutaneous) Histamine
Prostaglandin D
Leukotrienes C and D
Platelet activating factor or 1-O-alkyl-2-
acetyl-sn-glyceryl-3-phosphorylcholine
Complement system Anaphylatoxins C3a, C4a,C5a:
histamine
Hageman factor dependent bradykinin
pathway
Mononuclear cells Histamine-releasing factors,
chemokine