Download original study association between chronic autoimmune urticaria

ANALELE UNIVERSITĂŢII “DUNĂREA DE JOS” GALAŢI
MEDICINĂ
FASCICULA XVII, no 1, 2012
ORIGINAL STUDY
ASSOCIATION BETWEEN CHRONIC AUTOIMMUNE URTICARIA
AND THYROID AUTOIMMUNITY
Adriana Mihaela Tudose1, Florin-Dan Popescu1, Mariana Vieru1
,Florica Popescu2
1
Department of Allergology, “Carol Davila” University of Medicine and Pharmacy Bucharest, Romania
2
Department of Pharmacology, University of Medicine and Pharmacy Craiova, Romania
[email protected]
ABSTRACT
A subset of chronic idiopathic urticaria has been classified as autoimmune (presence of anti-IgE receptor
antibodies). The link between chronic urticaria(CU) and thyroid disease has been discussed. We evaluated the
association between urticaria and thyroiditis in romanian patients. From adult patients with CU(≥ 6-week
duration), presented during one-year period, we selected a group poorly controlled with high doses of H1
antihistamines and we performed autologous serum skin test (ASST) and screening levels for anti-thyroid
peroxidase(anti-TPO) antibodies, suggestive for Hashimoto tyroiditis, thyroid-stimulating hormone(TSH) and
thyroid hormones. Urticaria activity score(UAS) was used for monitoring disease activity, ASST and screening
for HIV-1 and -2, HBV and HCV serological markers were also performed in all patients, with written informed
consent obtained. From 238 patients with CU, 133 patients (55.88%) had positive ASST. 63 of them had
elevated levels of anti-TPO antibodies, 34 had Hashimoto's thyroiditis with euthyroid status, 20 had subclinical
hypothyroidism and 9 patients had clinical manifestations of hypothyroidism.. 105 patients had negative ASST
and of these only 5had elevated anti-TPO antibodies levels and only one had subclinical hypotiroidism.
Conclusion. In patients with autoimmune chronic urticaria, our data suggested that the frequency of thyroid
autoantibodies is significantly higher.
KEYWORDS: autoimmune urticaria, Hashimoto thyroiditis
In the last years a relationship between chronic
1. Introduction
urticaria
and
thyroid
disease
was
frequently
discussed. Chronic urticaria (CU) appears not to have
Urticaria is defined as a heterogeneous group
a direct link with atopic dermatitis or allergic rhinitis.
of disorders with a distinct characteristic, urticarial
IgE levels are usually within normal limits. No
lesion, with edema and vasodilation in the superficial
external allergen is involved in the initiation of the
dermis, papule of varying sizes surrounded by a reflex
pathomechanisms of urticarial lesions. A subset of
erythema, associated with itching or sometimes
CU patients had recently been classified as having
burning sensation, with or without angioedema.
autoimmune urticaria on the basis of two main
Urticarial papule appears rapidly and resolves within
findings: association with thyroid autoimmunity and
1-24 hours without residual lesions [1].
with anti-IgE and/or anti-IgE receptor antibodies [1].
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ANALELE UNIVERSITĂŢII “DUNĂREA DE JOS” GALAŢI
In
recent
guidelines,
the
incidence
FASCICULA XVII
of
antihistamines and we performed autologous serum
autoimmune urticaria is about 30–50% of CU and
skin test (ASST) and screening for anti-thyroid
may be associated with other autoimmune conditions,
peroxidase (anti-TPO) antibodies, suggestive for
especially autoimmune thyroiditis.
Hashimoto thyroiditis. Thyroid-stimulating hormone
At least one-third of all cases of CU are
(TSH) and thyroid hormones levels were also
autoimmune, with the possible association of thyroid
autoimmunity
with
or
without
determined in these patients.
clinically
ASST
was
performed
task
force
according
consensus
to
manifestations of hypothyroidism. In addition to the
EAACI/GA2LEN
report
presence of antithyroid antibodies (more frequent
guidelines [9]. Autologous serum was obtained by
than in the general population), these patients may
centrifugation from venous blood (cubital vein) in
have IgG antibodies targeted against circulating IgE
sterile Vacuette® serum tubes without clotting
or (much more often) against the epsilon subunit of
accelerator, allowed to clot for 30 min. A samples 50
the IgE high-affinity receptor (FcεR-I). The presence
μL autologous serum and 0.9% saline (from sterile
of such autoreactivity can be evaluated by skin testing
individual vials) separately was injected intradermally
with autologous serum, the intradermal autologous
into volar forearm exposed upward, with the 29-
serum skin test (ASST) [2].
gauge needle, at 15-degree angle at least 3-5 cm apart.
Early studies on the association of autoimmune
H1 antihistamines were withdrawn at least two days
thyroiditis with chronic urticaria have shown higher
and systemic corticosteroids for two months. If the
frequency of Hashimoto thyroiditis [3, 4]. The
average diameter of the autologous serum-induced
incidence of abnormal thyroid function, either
wheal was >1.5 mm of the saline-induced wheal, the
increased or decreased values of thyroxine levels, or
ASST was considered positive. ASST was considered
increased or decreased thyroid-stimulating hormone
strongly positive if the erythematous papule diameter
levels, or both, was estimated 12 ± 19% [5, 6]. A
was at least 5 mm higher than the control test at 30
detailed study of autoantibodies present in patients
min. Due to ethical reasons, screening for HIV-1 and
with CU revealed that antibodies against thyroid
-2, HBV and HCV serological markers were
peroxidase are significantly more common in urticaria
performed in all patients, with written informed
(20%) than in controls (0%), but broad non-specific
consent obtained.
autoimmunity seems not to be detected [7].
Many
patients
with
CU
have
Clinical monitoring of disease activity was
positive
performed by using urticaria activity score (UAS) of
autologous skin test [8]. The aim of our study was to
0-6 points, depending on the daily number of wheals
evaluate the association between autoimmune CU and
(none=0; <20=1; 21-50=2; >50/large, confluent=3)
autoimmune thyroid disease.
and the intensity of pruritus (none=0; mild=1;
moderate=2; intense=3) [1].
Patients who were included in the study were
2. Material and methods
assessed to have normal test results, such as complete
blood
From subjects referred to our clinic, during a
counts,
erythrocyte
sedimentation
rate,
12-month period, for evaluation of chronic urticaria
urinalysis, stool examination, hepatitis serology
(CU defined as urticaria with a more than six-week
negative
duration), we selected the group poorly controlled
patients were selected if values for rheumatoid factor
with high doses of oral second-generation H1
(RF) (immunonephelometery), anti-double-stranded
134
(immunochromatography).
In
addition,
ANALELE UNIVERSITĂŢII “DUNĂREA DE JOS” GALAŢI
FASCICULA XVII
DNA antibody (anti-dsDNA, latex agglutination),
detected sixty-three patients (47.36 %) having
Complement C3 and C4 (immmunonephelometery)
increased levels of anti-TPO antibodies (Figure 4).
were normal.
In both groups, ASST+ and ASST-, free
thyroxine (FT4) levels (normal, 0.7-1.48 ng/dL) and
thyroid-stimulating hormone (TSH) levels were
measured
by
chemiluminescent
immunometric
assays. The normal reference range for TSH was
0.35-4.94 μg/dL.
Anti-thyroid peroxidase (anti-TPO) antibodies
Figure 1. Sex ratio of patients with CU (n=238)
screened during one year-period (green = 29.84 %
males; blue = 70.16% females)
were determined by chemiluminescent immunometric
assay. The presence of anti-TPO antibodies and, in
addition thyroid dysfunction, were considered criteria
to meet the status of autoimmune thyroid disease. The
diagnosis of hypothyroidism was made by clinical
and laboratory criteria of FT4 < 0.7 ng/dL, TSH >
4.94
μg/dL.
Patients
were
classified
having
subclinical hypothyroidism if they were clinically
euthyroid
with
normal
FT4
levels,
but
had
significantly elevated TSH levels. The diagnosis of
hyperthyroidism has been based on the detection of
Figure 2. Percentage of patients with positive ASST
(n=133 patients from a total of 238 patients)
low serum TSH values (< 0.35 μg/dL) and elevated
serum levels of FT4 (> 1.48 ng/dL). All patients with
thyroid disease were examined by an endocrinologist.
3. Results
We screened 238 adult subjects with CU with a
mean age of 43.19 ± 15.4 years (limits 18; 82 years),
70.16% females (Figure 1). The group with CU was
selected from patients with no detected etiology. No
collagen tissue disease was suspected in this group
using clinical and immunological tests. The mean
duration of urticaria was 30.35 ± 24.11 months, and
patients were treated with standard or high doses of
oral nonsedating H1 antihistamines. 133 patients
(55.88%) were evaluated having a UAS score greater
Figure 3. Strong positive autologous serum skin
test (ASST)
than 3 points during pharmacotherapy and strong
From the group of one hundred and thirty-three
positive ASST (Figures 2 and 3), from which we
patients with positive ASST sixty-three had elevated
135
ANALELE UNIVERSITĂŢII “DUNĂREA DE JOS” GALAŢI
FASCICULA XVII
levels of anti-TPO antibodies (47.36%), thirty-four
greater than in the control group (4.76%), suggesting
had Hashimoto's thyroiditis with euthyroid status
a statistical correlation between autoimmune CU and
(25.56%), twenty had subclinical hypothyroidism
antithyroid antibodies.
(15,03%) and nine patients had clinical manifestations
of hypothyroidism (6,76%) (Figure 5). One hundred
and five patients had negative ASST. Only five
patients (4,76%) from this subgroup had elevated
anti-TPO antibodies levels (Figure 6) and only one
subject had subclinical hypotiroidism (0.95%).
Figure 6. Percentage of patients with increased
ATPO levels in the group of ASST-negative CU
Confidence interval calculated proved statistical
significance
(47.36+/-8%).
Risk
of
developing
autoimmune thyroiditis in those with positive
autolougus skin prick test was 47% while those with
Figure 4. Percentage of patients with increased
ATPO levels in the group with ASST-positive CU
ASST negative was 4%. Relative risk was 11.75.
Odds ratio was 18.
Thyroid
hormone
levels and autoimmune
thyroiditis status in patients with increased levels of
anti-TPO antibodies varied for thyroid hormone free
T4 between 0.42 and 1,44 ng/dL, for TSH ranged
between 1.33 and 5.6 microUI/mL.
4. Discussions
Figure 5. Percentage of patients with autoimmune
thyroid disease from patients with ASST-positive CU
The significative high prevalence of females
and the prevalence of the ASST positivity were
The values of anti-TPO antibodies ranged
consistent with results of similar studies [10, 11]. It is
between 8 UI/mL and 1000 UI/mL. RF and anti-ds
well known that autoimmune conditions have a higher
DNA antibodies were found to be negative in all
prevalence in females. The most striking sex
patients. Because patients were age-and sex-matched
differences are observed in Sjogren’s syndrome,
with control group (the group with ASST negative)
systemic lupus erythematosus, autoimmune thyroid
there was no statistical difference between the
disease (Hashimoto’s thyroiditis and well as Graves’
controls and the patients with respect to age and sex.
disease) and scleroderma, which represent a spectrum
Our study revealed that, in patients with
of diseases, in which women population is greater
autoimmune CU, the frequency of high thyroid
than 80% [12].
autoantibodies levels (47.36%) was significantly
136
ANALELE UNIVERSITĂŢII “DUNĂREA DE JOS” GALAŢI
FASCICULA XVII
The prevalence of the positive ASST in
in patients with thyroid autoimmunity is even less
patients with comorbidity urticaria-thyroiditis was
well established. There are conflicting reports on the
lower to than the one reported in a previous study
results of such hormonal therapy [6, 19]. Treatment
(56%) [18], but higher than that reported by other
with thyroxine was reported to alleviate the symptoms
authors (25%) [13].
of urticaria in some cases, with a concomitant
The
association
of
CU
with
thyroid
decrease in anti-thyroglobulin antibodies. Some
autoimmunity has been known for two decades, but
reports also advocated that patients with CU should
its frequency seems to vary in different reports. The
be screened for evidence of thyroid autoimmunity and
prevalence in series ranges from 12% to 33% [14,
that a trial of levothyroxine therapy for those who
15]. More recently, some studies have suggested that
have thyroid autoimmunity can contribute to clinical
there may be a link between CU and thyroid
improvement by the suppression of chronic thyroid
autoimmunity [3-5, 16, 17].
stimulation [20].
Our study revealed a higher frequency of
Finally, we consider that our data are
autoimmune thyroiditis in the group of patients with
consistent with the new European guidelines for
positive ASST, compared to those with CU, but with
patients with CU, that recommend evaluation for
negative ASST, thus suggesting a connection between
autoimmune thyroiditis [1], and underline the role of
the two conditions and explaining why the response
performing ASST in selected CU patients [21]. This
to systemic glucocorticosteroids seems to be better.
study offers original data for Romanian patients
We detected thyroid autoantibodies in 47.36%
presenting this association of autoimmune disorders,
of patients with autoimmune CU and this may be
having in mind that genetic predisposition also plays
considered
an important role in such immune dysregulation
a
relatively
high
percentage.
The
frequency of thyroid antibodies in the control group
conditions [22-25].
was 4.76%, when comparing with the previous
studies (0-5.6%) [18].
5. Conclusions
In our study, TSH levels were increased in
21.80% of patients with ASST-positive CU or
The recognition of functional autoantibodies in
autoimmune CU, compared to the group having
a group of CU patients developed a new concept of
negative ASST (0.95%).
autoimmune urticaria , therefore there is an important
Thyroid function tests are not sufficient to rule
role of autoimmune testing in CU. ASST remains a
out thyroid disease, and thyroid antibody tests should
baseline
be carried out in all patients with autoimmune CU.
diagnostic
test
for
autoimmune
CU.
Screening for thyroid autoimmunity and thyroid
Our study revealed a high incidence of the present of
function is advisable in all patients with chronic
anti-TPO antibodies in patients with autoimmune CU,
urticaria presenting positive ASST or autoimmune
compared to those who had negative ASST. We
CU for an early identification of patients requiring
consider that often it's just a matter of time before
specific treatment of underlying thyroid dysfunction,
thyroid dysfunction will have a clinical manifestation,
for a better control of CU and for a proper follow-up .
and more studies are required regarding this aspect.
References
While the association of CU and thyroid
autoimmunity is not completely understood, the
1. Leznoff A, Josse RG, Denberg J, et al. Association of
chronic urticaria and angioedema with thyroid autoimmunity. Arch
Dermatol 1983; 119: 636-40.
2. Leznoff A, Sussman GL. Syndrome of idiopathic chronic
potential use of levothyroxine in the treatment of CU
137
ANALELE UNIVERSITĂŢII “DUNĂREA DE JOS” GALAŢI
urticaria and angioedema with thyroid autoimmunity: a study of 90
patients. J Allergy Clin Immunol 1989; 84: 66-71.
3. Turktas I, Gokcora N, Demirsoy S, et al. The association of
chronic urticaria and angioedema with autoimmune thyroiditis. Int
J Dermatol 1997; 36: 187-90.
4. Kandeel AA, Zeid M, Helm T, et al. Evaluation of chronic
urticaria in patients with Hashimoto's thyroiditis. J Clin Immunol
2001; 21: 335-47.
5. Ryhal B, DeMera RS, Shoenfeld Y, et al. Are autoantibodies
present in patients with subacute and acute chronic urticaria? J
Invest Allergol Clin Immunol 2001; 11: 16-20.
6. Grattan CEH, Francis DM, Hide M, et al. Detection of
circulating histamine-releasing autoantibodies with functional
properties of anti IgE in chronic urticaria. Clin Exp Allergy 1992;
21: 695-704.
7. Cebeci F, Tanrikut A, Topcu E, et al. Association between
chronic urticaria and thyroid autoimmunity. European Journal of
Dermatology 2006; 4: 402-5.
8. Hein R. Chronic urticaria: impact of allergic inflammation.
Allergy 2002; 57(75): 19-24.
9. Hide M, Francis DM, Grattan CEH, Greaves MW.
Autoantibodies against the hight affinity IgE receptor as a cause
for histamine release in chronic urticaria. N Engl J Med 1993; 328:
1599-604.
10. Doutre MS. Physiopathology of urticaria. Eur J Dermatol
1999; 9: 601-5.
11. Heymann WR. Chronic urticaria and angioedema associated
with thyroid autoimmunity: Review and therapeutic implications. J
Am Acad Dermatol 1999; 40: 229-32.
12. Rumbyrt JS, Katz JL, Schocket AL. Resolution of chronic
urticaria in patients with thyroid autoimmunity. J Allergy Clin
Immunol 1995; 96: 901-5.
13. Zauli D, Grassi A, Ballardini G, Contestabile S, Zucchini
S, Bianchi FB. Thyroid autoimmunity in chronic idiopathic
urticaria: implications for therapy. Am J Clin Dermatol 2002; 3:
525-8.
14. *** Société Française de Dermatologie. Consensus
Conférence: Management of chronic urticaria. Eur J Dermatol
2003; 13: 385-92.
15. Ring J, Brockow K, Ollert M, Engst R. Antihistamines in
urticaria. Clin Exp Allergy 1999; 29: 31-7.
16. Saravanan P, Dayan CM. Thyroid autoantibodies. Endoc
Metab Clin Of North Am 2001; 30: 315-37.
17. Zauli D, Deleonardi G, Foderaro S, Grassi A, Bortolotti R,
Ballardini G, Bianchi FB. Thyroid autoimmunity in chronic
urticaria. Allergy Asthma Proc 2001; 22: 93-5.
18. Gaig P, Garcia-Ortega P, Enrique E, Richart C. Successful
treatment of chronic idiopathic urticaria associated with thyroid
autoimmunity. J Invest Allergol Clin Immunol 2000; 10: 342-5.
FASCICULA XVII
19. Verneuil L, Leconte C, Ballet JJ, Coffin C, Laroche D,
Izard JP, et al. Association between chronic urticaria and thyroid
autoimmunity: a prospective study involving 99 patients.
Dermatology 2004; 208: 98-103.
20. Palma-Carlos AG, Palma-Carlos ML. Chronic urticaria and
thyroid autoimmunity. Allerg Immunol 2005; 37: 143-6.
21. Weetman AP. Thyroid autoimmune disease. In: Breverman
LE, Utiger RD, eds. The Thyroid. A fundemental and Clinical
Text. Philadelphia: JB Lippincott, 1991: 1295-310.
22. Greaves M. Chronic urticaria. J Allergy Clin Immunol 2000;
105: 664-72.
23. Levy Y, Segal N, Weintrob N, Danon YL. Chronic urticaria:
association with thyroid autoimmunity. Arch Dis Child 2003; 88:
517-9.
24. Passeron T, Bahadoran P, Pugliese P, Lacour JP, Ortonne
JP. Lack of hypocomplementemia in chronic urticaria. Arch
Dermatol 2000; 136: 558-9.
25. Asero R. Sex differences in the pathogenesis of chronic
urticaria. J Allergy Clin Immunol 2003; 111: 425.
26. Beeson PB. Age and sex associations of 40 autoimmune
diseases. Am. J. Med. 1994; 96: 457-462.
27. Fusari A, Colangelo C, Bonifazi F, Antonicelli L. The
autologous serum skin test in the follow-up of patients with
chronic urticaria Allergy 2005; 60: 256–258.
28. Fusade PM, Vermeulen C, Roquette AM, Bayrou O,
Pecquet C, Leynadier F.Chronic urticaria, thyroid disease and the
autologous serum skin test. J Allergy Clin Immunol 2002; Jan:
S124.
29. Zuberbier T, Asero R, Bindslev-Jensen C, Walter
Canonica G, Church MK, Giménez-Arnau A, Grattan CE,
Kapp A, Merk HF, Rogala B, Saini S, Sánchez-Borges M,
Schmid-Grendelmeier P, Schünemann H, Staubach P, Vena
GA, Wedi B, Maurer M; Dermatology Section of the European
Academy of Allergology and Clinical Immunology; Global
Allergy and Asthma European Network; European Dermatology
Forum;
World
Allergy
Organization.
EAACI/GA2LEN/EDF/WAO guideline: definition, classification
and diagnosis of urticaria. Allergy. 2009; 64(10):1417-26.
30. Popescu FD, Tudose AM, Vieru M, Ionete OM, Paunescu
A, Popescu F. Clinical experience with autologous whole blood
injections in chronic urticaria, 3rd International Consensus
Meeting on Urticaria and 12th Meeting of the AGMZB, Mast Cell
and Basophil Section of the ADF, 2008, Joint Meeting Berlin,
Abstract Book, p. 40.
31. Tudose, A; Popescu, F; Vieru, M; Popescu, F Screening for
anti-thyroid peroxidase antibodies in Romanian patients with
chronic autoreactive urticaria, Allergy Volume 65, Issue
Supplement s92, p448.
138