EXPERIMENTAL AND THERAPEUTIC MEDICINE 17: 2603-2613, 2019

Association of positive and negative autologous serum skin test

responses with clinical features of chronic spontaneous urticaria
in Asian patients: A systematic review and meta‑analysis
XUE LI NIU1*, LI LI ZHU2*, MEI HUI SHI1, YU JING ZHANG1, XING HUA GAO1 and RUI QUN QI1

1
Department of Dermatology, No. 1 Hospital of China Medical University and Key Laboratory of Immunodermatology,
Ministry of Health and Ministry of Education, Shenyang, Liaoning 110001; 2Department of Dermatology,
The People's Hospital of Liaoning Province, Shenyang, Liaoning 110016, P.R. China

Received March 11, 2018; Accepted October 3, 2018

DOI: 10.3892/etm.2019.7266

Abstract. Previous studies on the correlation between positive that the ASST provides an effective means of predicting
autologous serum skin test (ASST) responses and the clinical urticaria activity and recurrence in CSU patients.
features of patients with chronic spontaneous urticaria (CSU)
have provided conflicting results. To evaluate the significance Introduction
of ASST responses in CSU, a variety of databases were
searched from inception to March 2018 to identify relevant Chronic urticaria (CU), more commonly referred to as hives, is
studies on CSU. Data were analyzed with use of the Cochrane a frequently occurring condition that may persist for >6 weeks.
Collaboration's Review Manager 5.2. Multiple relevant factors CU is subdivided into chronic autoimmune urticaria (CAU),
of CSU were evaluated by calculating the weighted mean chronic spontaneous urticaria (CSU) and physical urticaria
difference, odds ratio and 95% confidence interval. The results (PU), and CSU accounts for 35% of CU patients (1). The
indicated that CSU cases with positive ASST responses had mechanisms of CSU are complex and may be triggered by
higher urticaria activity scores and higher levels of total serum drugs, physical stimuli, as part of inflammatory or inherited
immunoglobulin E than CSU cases with negative responses diseases, or may be idiopathic in nature. Over half of all CSU
in the ASST. In addition, a positive ASST response was cases are thought to involve autoimmune mechanisms (2).
more likely to be accompanied with the presence of thyroid The autologous serum skin test (ASST) provides an in vivo
autoantibodies and angioedema. An increased prevalence of assay for diagnosing autoimmune urticaria. The ASST
CSU was identified in females, who were more likely to have procedure consists of collecting an autologous serum sample
a positive response in the ASST. It was also indicated that a from the CU patient, followed by injection of this sample into
greater incidence of positive ASST responses was present in an area of normal skin. A positive response is indicated by
CSU patients as compared with that in healthy controls. No the appearance of an erythematous papule within 30 min
statistically significant differences were obtained between following injection (3).
positive and negative ASST responses with regard to age and The ASST serves as an effective clinical screening tool
duration of disease. Based on these results, it was concluded and has become the established method for the detection of
functional circulating auto‑antibodies in patients with CU.
The negative predictive value (NPV) of the ASST has been
reported to be 82.5±14% (4). This means that in CU patients
with a negative response to the ASST, no functional circu-
lating auto‑antibodies were present in their serum. However,
Correspondence to: Professor Xing Hua Gao or Dr Rui Qun Qi, a positive ASST response may occur in patients with allergic
Department of Dermatology, No. 1 Hospital of China Medical diseases and even in healthy controls. Therefore, to confirm
University and Key Laboratory of Immunodermatology, Ministry the presence of an autoimmune disorders, a quantitative
of Health and Ministry of Education, 155N Nanjing Road, Heping,
analysis is required (5). It has been reported that in cases with
Shenyang, Liaoning 110001, P.R. China
positive ASST responses, a higher urticaria activity score
E‑mail: gaobarry@hotmail.com
E‑mail: xiaoqiliumin@163.com (UAS), longer disease durations, lower scores on quality of
life questionnaires and increased potentials for accompanying
*
Contributed equally angioedema were present (6,7).
CU is a benign disease, has an autoimmune basis in 40%
Key words: autologous serum skin test, chronic urticaria, of cases (8) and is more prevalent in females. Immunoglobulin
meta‑analysis, angioedema, urticaria activity score (IgE) has an indispensable role in the occurrence of CSU (9,10),
with autoantibodies targeting high‑affinity IgE receptors
(FcεRI) or IgE in patients with CSU (11). Thyroid disease is
2604 NIU et al: CLINICAL IMPLICATIONS OF AUTOLOGOUS SERUM SKIN TEST IN CHRONIC URTICARIA

the most commonly reported autoimmune condition in patients for continuous variables across studies that were measured
with CSU. CSU patients with coexisting thyroid autoimmunity on the same scale. Dichotomous variables were assessed by
tend to have a more severe and prolonged course of their urti- calculating the odds ratio (OR). All data were expressed as
caria than those without thyroid autoimmunity. A recent study the WMD or OR along with their associated 95% confidence
has indicated that 9.8% of CU patients had hypothyroidism, intervals (CI). Heterogeneity between studies was tested by
compared with 0.6% in the control group (12). CU and thyroid using I2 tests. P<0.1 or I2>50% was considered to indicate a
disease may be interlinked, and the latter may promote the high degree of heterogeneity between studies. If a significant
occurrence of CU (13). Previous studies have produced contro- heterogeneity was present (P<0.1), the random effects model
versial results about the associations between positive ASST was selected for heterogeneous outcomes (P<0.05 or I2≥50%),
responses and the clinical features of CSU. Therefore, the otherwise, the fixed effects model was performed for homoge-
current meta‑analysis was undertaken to clarify the associa- neous outcomes (P≥0.05 and I2<50%). P<0.05 was considered
tion between ASST and CSU. to represent statistically significant differences.
A sensitivity analysis was performed by removing studies
Materials and methods one at a time to confirm the robustness of the results. Finally,
publication bias in the analysis was determined using a funnel
Literature search. The PubMed, Embase, Medline, Ovid, plot and Egger's regression test.
Cochrane Library, China National Knowledge Infrastructure,
China Biology Medicine and Wangfang databases, as well Results
as the VIP Database for Chinese Technical Periodicals were
searched to identify relevant studies involving ASST and Study characteristics. A total of 1,629 relevant studies were
clinical features of CSU. This search included the period from retrieved. After removal of duplicates by title, 851 articles were
inception of the database until March 2018. The search strategy further screened. Following a careful review of these studies,
combined the following terms: ‘Autologous serum skin test’ the full text of 39 studies were assessed. Finally, 16 articles
and ‘chronic spontaneous urticaria’. There was no restriction met the inclusion criteria and were included in the systematic
regarding language or the type of article. An additional manual review (6,7,14‑27). The selection process for these studies is
search was performed by screening the references listed in key summarized in Fig. 1. A total of 2,554 patients, including
publications retrieved in this search. 1,284 with positive and 1,270 with negative ASST results were
assessed. The characteristics of these patients are presented
Inclusion and exclusion criteria. An overall literature search in Table I. The publication year ranged from 2005 to 2017. Of
was performed and relevant studies were screened inde- note, the search of all databases for eligible articles revealed
pendently by two reviewers. Eligible studies were selected that the region of all studies retrieved was Asia, including
based on the following criteria: i) Study design: Prospective China, Thailand, Korea, India, Taiwan and Japan.
observational study. ii) Patients with clinically defined CU.
iii) Information on responses to the ASST. iv) Information on Quality assessment of included studies. Detailed results
at least one of the following parameters: Average age, duration regarding the quality assessment are summarized in Table I.
of disease, UAS, angioedema, anti‑thyroid antibodies, total All included studies were prospective observational studies.
serum IgE, erythrocyte sedimentation rate and allergic rhinitis. The present meta‑analysis was restricted to studies with a low
The exclusion criteria were as follows: i) Experiments on risk of bias (NOS ≥7), and the entire analysis was replicated
animal models; ii) cases lacking a definitive diagnosis of CU; following removal of the most influential study on the basis of
iii) intervention trials; iv) reports lacking relevant/sufficient its weight.
data; v) duplicate publications.
Comparison of the influence of ASST responses on CSU cases
Data extraction. Relevant data were extracted by two reviewers and heathy controls. Of all studies reviewed, 6 provided data on
independently. Information included in the forms prepared by ASST responses in heathy controls (15,19,21,23,25). Statistical
these reviewers comprised the following: First author's name, analysis revealed a high degree of homogeneity across studies
publication year, number of patients, mean age, duration of (P=0.18, I2=34%). Meta‑analysis using the fixed‑effects model
disease, results of ASST, UAS, angioedema, anti‑thyroid indicated that CSU cases were more frequently associated with
antibodies, total serum IgE and allergic rhinitis. positive ASST responses than the healthy controls (P<0.01,
OR=17.16, 95% CI, 9.31‑31.63; Fig. 2).
Assessment of study quality. Quality assessment of included
studies was independently performed and crosschecked by Comparison of age, duration of disease and UAS in
two reviewers using the Newcastle‑Ottawa scale (NOS), which positive and negative ASST cases. Of all 16 studies,
assesses bias on a scale of up to nine stars; >6 stars on the NOS 14 (6,7,14,18,20,24,26,27) and 10 (6,14,16,17,19,22,24,26,27)
were regarded as indicative of a high quality. provided data on age and duration of disease, respectively,
in the two groups. A significant heterogeneity was present
Statistical analysis. The meta‑analysis was performed using across the studies (age: P<0.001, I2=95%; duration: P<0.001,
Review Manager 5.2 (the Cochrane Institute, London, UK). I 2 =83%), necessitating use of the random‑effects model.
The inverse‑variance test was applied for continuous variables The meta‑analysis indicated that the two groups displayed
and the Mantel‑Haenszel test for examination of dichotomous no statistically significant differences in age (P= 0.96,
variables. The weighted mean difference (WMD) was used WMD= 0.11, 95% CI, ‑4.31 to 4.52; Fig. 3) and duration
Table I. Characteristic and methodological quality of included studies.

No. of subjects
No. of ‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑ Duration Anti‑ No. of NOS
First author Year Area samples Group Patients Controls Age (years) (months) UAS IgE (IU/ml) thyroid Angioedema males score (Refs.)

Alpay A 2013 Japan 50 N1 31 5 35.64±67.20 5 (31) 16 (31) 8 (19)

N2 19 45 36.24±50.40 2 (19) 10 (19)
Boonpiyathad T 2016 Thailand 128 N1 78 32.60±8.30 6.16±7.26 3 (78) 19 7 (14)
N2 50 38.10±10.90 5.76±6.60 4 (50) 16
Chen MC 2008 China 100 N1 58 0 8.03±1.50 8 (25)
N2 42 42 7.07±1.50
Kim JH 2016 Korea 138 N1 69 37.00±11.75 6.00±23.63 9.00±2.5 120.00±296.20 16 8 (17)
N2 69 41.00±13.25 5.50±59.63 10.00±2.50 113.00±247.50 21
Krupashankar 2012 India 80 N1 47 33.81±12.04 21.70±30.65 8 (48) 24 (47) 19 7 (22)
DS N2 33 37.58±14.36 17.42±18.63 5 (62) 9 (33) 17
Kumar YH 2016 India 110 N1 48 28.54±13.50 7 (47) 13 (48) 15 7 (20)
N2 62 31.55±14.43 1 (33) 8 (62) 22
Lee MF 2014 Taiwan 40 N1 20 37.00±7.25 174.80±49.50 2 (18) 5 8 (18)
N2‑ 20 46.60±15.00 129.10±16.60 1 (19) 10
Li MM 2016 China 136 N1 54 38.52±12.53 45.27±65.67 7.60±4.30 171.20±331.10 9 (54) 10 7 (26)
N2 82 36.60±11.83 35.24±42.54 7.60±3.90 143.90±294.10 16 (82) 24
Aktar S 2015 Japan 50 N1 23 3 35.65±9.12 3.09±2.02 5 7 (15)
N2 27 20 29.59±9.66 3.15±1.74 13
Song ZQ 2013 China 862 N1 399 35.50±8.80 21.23±10.62 4.20±0.70 8 (6)
N2 463 23.50±7.60 27.58±18.63 3.80±0.50
Sun WL 2005 China 82 N1 29 38.30±12.30 41.80±51.40 14.07±2.25 8 (29) 16 (29) 6 7 (27)
EXPERIMENTAL AND THERAPEUTIC MEDICINE 17: 2603-2613, 2019

N2 53 33.70±14.40 32.60±40.00 13.13±3.00 3 (53) 13 (53) 15

Yadav S 2013 India 80 N1 40 4 32.50±8.75 6.80±1.20 8 (40) 7 (21)
N2 40 40 33.00±8.75 6.20±1.40 6 (40)
Yang SL 2016 China 79 N1 43 0 39.23±12.24 55.66±38.10 14.64±2.11 14 7 (24)
N2 36 20 38.72±12.65 23.68±20.00 13.16±1.12 16
Ye YM 2016 Korea 75 N1 17 38.20±11.80 30.50±26.50 9.50±4.10 238.30±306.60 6 (17) 6 (17) 5 7 (16)
N2 50 41.10±12.40 13.00±89.50 10.10±3.60 250.20±390.70 9 (47) 21 (50) 19
Zhong H 2014 China 390 N1 261 34.70±13.80 4.00±1.30 91 (261) 71 7 (7)
N2 129 32.30±15.30 3.40±1.60 16 (129) 51
2605
2606 NIU et al: CLINICAL IMPLICATIONS OF AUTOLOGOUS SERUM SKIN TEST IN CHRONIC URTICARIA

score (Refs.)

Values are presented as number, mean ± standard deviation or number of positive subjects (total number of subjects). N1, positive autologous serum skin test response; N2, negative autologous serum skin
(23)
NOS

8
37
No. of
thyroid Angioedema males

25
Anti‑

7.30±2.00
6.70±1.70
IgE (IU/ml)
Duration
UAS

Figure 1. Flow diagram depicting the process of the selection of studies for
the present meta‑analysis. NOS, Newcastle‑Ottawa scale.
36.23±15.14 34.40±73.07
34.94±13.27 24.17±13.17
(months)

(P=0.08, WMD=5.48, 95% CI, ‑0.71 to 11.68; Fig. 4). A

subgroup analysis regarding patient age was then performed,
in which patients were stratified by region. Results from
China and India indicated that the two groups exhibited
no difference in age (China: P=0.15, WMD=3.95, 95% CI,
test response; UAS, urticaria activity score; Ig, immunoglobulin; NOS, Newcastle‑Ottawa scale.
samples Group Patients Controls Age (years)

‑1.49 to 9.39; India: P=0.18, WMD=‑1.88, 95% CI, ‑4.63 to

No. of ‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑‑

0.87). Of note, the results from Korea, Thailand and Taiwan

indicated that a positive ASST response was associated with
younger age (Korea: P=0.04, WMD=‑3.68, 95% CI, ‑7.21 to
‑0.16; Taiwan: P=0.01, WMD=‑9.6, 95% CI, ‑16.9 to ‑2.30;
No. of subjects

Thailand: P=0.002, WMD=‑5.50, 95% CI, ‑9.04 to ‑1.96),

0
30

while the opposite result was obtained in Japan (P= 0.02,

WMD=6.06, 95% CI, 0.85‑11.27; Fig. 3). Another subgroup
analysis was performed with stratification by duration of
67
87

disease (≤30 vs. >30 months). It was revealed that in patients

with a duration of disease of ≤30 months, the disease dura-
tion was not significantly associated with the result of the
N1
N2

ASST (P=0.59, WMD=‑1.52, 95% CI, ‑7.03 to 3.99), while

in those with a duration of disease of >30 months, a positive
ASST response was associated with a significantly increased

154

duration of disease as compared with that in patients with a

negative ASST response (P=0.002, WMD=15.93, 95% CI,
56.64‑26.22; Fig. 4).
A total of 11 studies provided data on UAS (6,7,15,17,21,23,27).
Area

2017 China

Statistically significant heterogeneity was present across these

studies (P= 0.01, I 2 =59%), again resulting in the use of the

random‑effects model. The meta‑analysis revealed that the
Year
Table I. Continued.

positive ASST response group had a higher UAS than that

of the negative ASST response group (P<0.001, WMD=0.42,
95% CI, 0.35‑0.50; Fig. 5). Therefore, a subgroup analysis
First author

Zhou PM

was performed based on the range of UAS as estimated by

employing different guidelines, including European (28) and
 EXPERIMENTAL AND THERAPEUTIC MEDICINE 17: 2603-2613, 2019 2607

Figure 2. Probability of a positive autologous serum skin test response for subjects with chronic spontaneous urticaria vs. healthy controls. Blue square, weight
of each study; black diamond, weighted mean difference; horizontal lines, 95% CI of each study; CI, confidence interval; M‑H, Mantel‑Haentzel; df, degrees
of freedom.

Figure 3. Difference in age between chronic spontaneous urticaria cases with positive vs. negative ASST responses. Green square, weight of each study; black
diamond, weighted mean difference; horizontal lines, 95% CI of each study; SD, standard deviation; IV, inverse variance; CI, confidence interval; ASST,
autologous serum skin test; df, degrees of freedom.
2608 NIU et al: CLINICAL IMPLICATIONS OF AUTOLOGOUS SERUM SKIN TEST IN CHRONIC URTICARIA

Figure 4. Differences in duration of chronic spontaneous urticaria in cases with positive vs. negative ASST responses. Green square, weight of each study;
black diamond, weighted mean difference; horizontal lines, 95% CI of each study; SD, standard deviation; IV, inverse variance; CI, confidence interval; ASST,
autologous serum skin test; df, degrees of freedom.

Korean guidelines (29). The results of this subgroup analysis autoantibodies (P<0.01, OR=1.87, 95% CI, 1.19‑2.94; Fig. 7)
also indicated that the positive ASST response group had a than a negative ASST result.
higher UAS than the negative ASST response group [UAS Data from 7 studies provided information on angioedema
(0‑6): P<0.001, WMD= 0.41, 95% CI, 0.33‑0.49; UAS (0‑9): in the two groups. As the results on angioedema displayed
P<0.001, WMD=0.77, 95% CI, 0.36‑1.18; UAS (0‑18): P=0.00, a statistically significant heterogeneity across studies
WMD=1.18, 95% CI, 0.57‑1.80]. However, the results of UAS (P= 0.03, I 2 =57%), it was necessary to use the random‑effects
of 0‑12 was at the verge of statistical significance, however it model. Meta‑analysis revealed that a positive ASST result
was not statistically significant (P= 0.05, WMD= 0.60, 95% CI, was associated with a higher risk of angioedema than that
0.00‑1.20, and an inverse result was observed for UAS of 0‑15 of a negative ASST result (P=0.03, OR=1.92, 95% CI,
(P=0.04, WMD=‑0.73, 95% CI, ‑1.41 to ‑0.05). In addition, 1.08‑3.40; Fig. 8). Angioedema is a subjective index of
two studies provided the median and range of UAS but no urticaria and manifests in a relatively short‑lived edema
standard deviation (SD) (25,27). The SD was then calculated in the skin. The occurrence of angioedema is affected by
using an established formula (30). inherited and environmental factors; furthermore, physical
stimulators, including shock and pressure, may also induce
Comparison of total serum IgE, angioedema and anti‑thyroid angioedema (31). As a result, a substantial heterogeneity in
autoantibodies in positive and negative ASST groups. Of all angioedema data may be present.
studies included in the present review, 4 (16‑18,26) provided
data on total serum IgE and 8 (16,18‑22,26,27) on the presence Sex differences among subjects with positive ASST responses.
of thyroid autoantibodies in the two groups. Statistical analysis An included study demonstrated that females are more likely
indicated that a significant homogeneity was present across to have a positive ASST response as rates of ASST were
these studies (serum total IgE: P= 0.78, I 2=0%; anti‑thyroid 78% and 22% in females and males, respectively (15). Of all
autoantibodies: P= 0.38, I 2 =7%). Meta‑analysis using the studies included in the present review, 12 (7,14,18,20,22,24,27),
fixed‑effects model indicated that a positive ASST result was which accounted for 1462 cases, contained 756 cases with posi-
associated with higher levels of total serum IgE (P<0.001, tive responses to ASST. Of these 756 cases, 210 were males
WMD=41.99, 95% CI, 20.40 to 63.58; Fig. 6) and thyroid and 546 were females. Statistical analysis of positive ASST
 EXPERIMENTAL AND THERAPEUTIC MEDICINE 17: 2603-2613, 2019 2609

Figure 5. Differences in UAS in chronic spontaneous urticaria cases with positive vs. negative ASST responses. Green square, weight of each study; black
diamond, weighted mean difference; horizontal lines, 95% CI of each study; SD, standard deviation; IV, inverse variance; CI, confidence interval; ASST,
autologous serum skin test; df, degrees of freedom; UAS, urticaria activity scores.

Figure 6. Differences in serum total immunoglobulin E levels in chronic spontaneous urticaria cases with positive vs. negative ASST responses. Green square,
weight of each study; black diamond, weighted mean difference; horizontal lines, 95% CI of each study; SD, standard deviation; IV, inverse variance; CI,
confidence interval; ASST, autologous serum skin test; df, degrees of freedom.

responses in CSU cases indicated that a statistically significant detailed results of the meta‑analysis for the above indexes are
homogeneity was present across studies (P=0.97, I2=0%), and presented in Table I.
the fixed‑effects model was therefore used. The meta‑analysis
revealed that females had a higher prevalence of positive ASST Sensitivity analysis. Studies that failed to satisfy the criterion
responses (P<0.001, OR=0.63, 95% CI, 0.50‑0.79; Fig. 9). The of high quality were excluded from the present review. In
2610 NIU et al: CLINICAL IMPLICATIONS OF AUTOLOGOUS SERUM SKIN TEST IN CHRONIC URTICARIA

Figure 7. Probability of the presence of anti‑thyroid antibodies in chronic spontaneous urticaria cases with positive vs. negative ASST responses. Blue square,
weight of each study; black diamond, weighted mean difference; horizontal lines, 95% CI of each study; M‑H, Mantel‑Haentzel; CI, confidence interval; ASST,
autologous serum skin test; df, degrees of freedom.

Figure 8. Probability of angioedema in chronic spontaneous urticaria cases with positive vs. negative ASST responses. Blue square, weight of each study;
black diamond, weighted mean difference; horizontal lines, 95% CI of each study; M‑H, Mantel‑Haentzel; CI, confidence interval; ASST, autologous serum
skin test; df, degrees of freedom.

addition, a sensitivity analysis was applied for each index inconformity in publication bias, the funnel plots had typical
involving ASST comparisons. The sensitivity analysis shapes, and the funnel plot of anti‑thyroid autoantibodies is
demonstrated that the results obtained using the random‑ and presented in Fig. 10.
fixed‑effects models were in accordance with each study
included in the review. These results suggested that no indi- Discussion
vidual studies significantly affected the pooled results. This
indicated that the meta‑analysis performed provided reliable To the best of our knowledge, the present study is the first
results. systematic review comparing ASST responses in patients
with CSU. The results obtained by the meta‑analysis suggest
Detection of publication bias. An analysis of publication bias that cases with positive ASST responses had higher UAS
was performed by using Egger's regression test. The results and higher levels of serum total IgE than those of cases with
indicated that no publication bias was present regarding the negative ASST responses. In addition, cases with positive
UAS and sex differences among patients with positive ASST responses to ASST were more likely to have accompanying
responses (UAS: Z=‑2.18, P=0.06; sex differences among angioedema and were positive for thyroid autoantibodies. CSU
patients with positive ASST response: Z=‑0.73, P=0.48). was more prevalent in females, who were also more likely to
However, publication bias was present with regard to age exhibit a positive response to ASST. It was also confirmed
and duration of CSU (age: Z=‑3.93, P=0.002; duration of that a greater incidence of ASST was present in CSU patients
CSU: Z=4.23, P=0.003). Although the above results revealed as compared with that in heathy controls. No statistically
that studies included in the present review displayed an significant differences were present between cases with
 EXPERIMENTAL AND THERAPEUTIC MEDICINE 17: 2603-2613, 2019 2611

Figure 9. Probability of a positive autologous serum skin test response in males vs. females with chronic spontaneous urticaria. Blue square, weight of each
study; black diamond, weighted mean difference; horizontal lines, 95% CI of each study; M‑H, Mantel‑Haentzel; CI, confidence interval; df, degrees of
freedom.

CU have significantly elevated levels of total IgE and levels

of serum total IgE are associated with disease severity and
duration (36). The severity of CSU was also identified to be
associated with a positive response in the ASST (37), which
is in accordance with the results of the present meta‑analysis.
CSU is linked with thyroid diseases, which are the most
commonly reported autoimmune condition in patients
with CSU. Patients with thyroid dysfunction and CSU have
a more severe and prolonged course of urticaria than those
without thyroid dysfunction. A significantly greater number
of anti‑thyroid antibodies are present in CSU patients. Even
in clinically euthyroid CSU patients, anti‑thyroid antibodies
remain present and are considered to be associated with CSU.
Thyroid disease may worsen urticaria through activation of
the complement system (2).
CU is characterized by mast/basophil cell activation,
which initiates an inflammatory response. Sex hormones
Figure 10. Funnel plot of studies on anti‑thyroid autoantibodies for chronic modulate immune and inflammatory cell functions, including
spontaneous urticaria cases with positive and negative autologous serum skin mast cell secretion. Of note, urticaria may be associated with
test responses. OR, odds ratio; SE, standard error; log OR, logarithm of OR.
certain diseases and conditions associated with hormonal
changes, including endocrinopathy, the menstrual cycle, preg-
nancy, menopause and hormonal contraceptives or hormone
positive vs. negative responses to ASST with regard to patient replacement therapy. Dehydroepiandrosterone (DHEA) is a
age and duration of disease. modulator of endocrine and immune functions and depletion
Angioedema, which is the clinical manifestation of urti- of DHEA may lead to adverse events (38). Serum concentra-
caria, develops when urticaria is located within the subcutis. tions of DHEA sulfate in CSU patients are significantly lower
It is a syndrome characterized by a sudden and limited than those in healthy subjects and are associated with positive
subcutaneous and/or submucous swelling. Angioedema in responses to ASST (39). This is in accordance with the results
CU is caused by a non‑specific histamine release from acti- of the present meta‑analysis, which indicate a female predomi-
vated mast cells (32). The occurrence of angioedema in CU, nance for CSU and a positive response in the ASST (6‑8,15).
while not an indication for disease severity, is associated Although the average NPV of the ASST was 92.8%, a
with a longer duration of urticarial disease. Non‑steroidal negative ASST was identified as a significant determinant
anti‑inflammatory drugs and/or systemic corticotherapy are of urticaria remission and a negative ASST serves as a
classic triggers of angioedema in CU (33). Mast cells may be good predictor for achieving urticaria remission within
activated primarily by IgE‑dependent (allergen, anti‑IgE) as 2 years (8,14,40). A positive ASST response is a significant
well as by IgE‑independent mechanisms (34). Increased levels predictor of CSU in controls (14).
of IgE are thought to provoke urticaria. Auto‑antibodies for While the studies included in the present meta‑analyses
IgE and the α‑chain of FcεRI contribute to the occurrence of were selected based on strict inclusion and exclusion criteria,
CU (35). It has been reported that one third of patients with certain unavoidable limitations and bias remain. As compared
2612 NIU et al: CLINICAL IMPLICATIONS OF AUTOLOGOUS SERUM SKIN TEST IN CHRONIC URTICARIA

with a randomized controlled trial, the quality of observa- content. All authors have read and approved the final version
tional studies is low, which represents a limitation of the of the manuscript prior to submission.
present meta‑analysis. However, all subjects enrolled in the
present meta‑analysis were patients with CU who voluntarily Ethics approval and consent to participate
underwent an ASST. The major observational endpoints
were UAS, serum total IgE and anti‑thyroid autoantibodies, Not applicable.
all of which are objective parameters. Furthermore, all
of the studies included were on Asian populations, which Patient consent for publication
is a cause of publication bias. Although ASST has a high
specificity to test for functional autoantibodies, their absence Not applicable.
has a high specificity for CU. According to the European
expert consensus from 2009 (8), the value and meaning of Competing interests
the ASST remains to be fully established. Furthermore, skin
testing requires the collection of venous blood and separa- The authors have no competing interests to declare.
tion of serum prior to hypodermic injection. It is essential
that failsafe precautions are taken to ensure that the patient's References
own serum is used for skin testing and aseptic procedures
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