Autoimmune Biomarkers and Disease Severity in Chronic Idiopathic Urticaria

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

Sadudee (Boonmee) Klakayan, MD

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)

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%

• 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)

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

• 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


• 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.


• 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


Objective
• Aimed to characterize the association
between CU, autoimmune diseases, and
autoimmune/inflammatory serologic markers
in a large unselected population


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


• 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

• 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

• 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

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


With in 10 yr


Other autoimmune disease and CU

• 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

• 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

Serologic and Labortory markers and CU

Abnormal high

306 CU pt.with hypothyroidism have Antithyroid Ab( ATG,ATPO)


• 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


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

• 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

• 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.)

• 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

• 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

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

• 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

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.


• 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


• 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)


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


Results
• Percentage of patients with positive autoimmune
biomarkers


Results
• Autoimmune biomarkers and disease severity

80%

46%
50%
30%


Results
• Test characteristics of combinations of autoimmune
biomarkers
4.5
2.3

3.1


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


• 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

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

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