Clinical Communications
Long-term combinations and updosing
of second-generation H1-antihistamines
show efficacy and safety in the
treatment of chronic spontaneous
urticaria: A multicenter real-life pilot
study
Liming Zhang, PhDa, Jian Wu, PhDa, Yumeng Qi, MSa,
Hong Zhu, MSb, Xu Yao, MDb, Mengmeng Li, MSc,
Jingyi Li, MDc, Zaipei Guo, MDc, Xiangyang Su, PhDd,
Wei Lai, MDd, Siyu Hao, MSe, Yuzhen Li, MD, PhDe,
Yang Li, MSf, Chunli Yao, PhDf, Fuqiu Li, PhDf,
Huiping Wang, MDg, Quanzhong Liu, PhDg, Hai Long, PhDh,
Qianjin Lu, PhDh, Xinghua Gao, MD, PhDa,
Hongduo Chen, MDa, and Ting Xiao, MD, PhDa
Clinical Implications

This study provides supportive evidence for the
American guideline for the long-term efficacy and safety
of multiesecond-generation H1-antihistamine (sgAH)
combinations and mono-sgAH updosing regimens for
chronic spontaneous urticaria, whereas H2-
antihistamines and/or montelukast further enhance the
efficacy of these 2 regimens.
Second-generation H1-antihistamines (sgAHs) at licensed
doses are recommended as first-line treatment for chronic
spontaneous urticaria (CSU, also known as chronic idiopathic
urticaria [CIU]) based on the EAACI/GA2LEN/EDF/WAO
guideline (international guideline) and the American Academy of
Allergy, Asthma and Immunology/American College of Allergy,
Asthma and Immunology Joint Task Force (American guide-
line).1,2 However, the 2 guidelines differ with regard to second-
line treatment, with the international guideline recommending
updosing sgAHs up to 4-fold,1 whereas the American guideline
recommends dose advancement of sgAH, along with the addition
of another sgAH, an H2-antihistamine, a leukotriene receptor
antagonist (LRA), or a first-generation H1-antihistamine.2
Some studies have reported acceptable short-term efficacy and
safety of updosing of sgAHs for patients with CSU not
responding to standard doses of sgAHs.3-5 However, limited
information exists regarding long-term efficacy and safety of
multi-sgAH combinations and mono-sgAH updosing for CSU.
In this study, we assessed the long-term efficacy and safety of
multi-sgAH combinations and mono-sgAH updosing regimens
for patients with CSU.
Multi-sgAH combinations or mono-sgAH updosing regimens
comprised second-step treatments. H2-antihistamines (ranitidine or
famotidine) and/or montelukast were added as third-step treat-
ments. Cyclosporine and tripterygium wilfordii polyglycoside were
used as fourth-step treatment. First-generation H1-antihistamines
were not used. The ethical approval, classification of control of
disease activity and remission state at week 52, detailed treatment
regimens, laboratory examinations, and statistical methods are
described in this article’s Online Repository at www.jaci-inpractice.
org.
Totally, 169 patients were recruited (Table E1, available in
this article’s Online Repository at www.jaci-inpractice.org). Sixty
(35.5%), 82 (48.5%), 22 (13.0%), and 3 (1.8%) were
completely controlled with first-, second-, third-, and fourth-step
treatments, respectively (Table E2 and Figure E1, available in
this article’s Online Repository at www.jaci-inpractice.org).
The characteristics of patients with CSU completely
controlled by first- and third-step treatment and the character-
istics of patients between mono-updosing sgAH regimens and
multicombinating sgAH regimens are described in Tables E3 and
E4, respectively (available in this article’s Online Repository at
www.jaci-inpractice.org). The characteristics between the 2-fold
complete group (2-fold and eq 2-fold), the 4-fold complete
group (4-fold and eq 4-fold), and the fourth-step complete group
and the characteristics of the 5 patients who required fourth-step
treatment are described in Tables E5 and E6, respectively
(available in this article’s Online Repository at www.jaci-
inpractice.org).
In the 22 patients completely controlled by third-step treat-
ment, 8 were treated by the addition of H2-antihistamines, 3 by
montelukast, and 11 by both (Table E2, available in this article’s
Online Repository at www.jaci-inpractice.org). It took averagely
3.9 and 5.0 weeks before we added H2-antihistamines and
montelukast to the 4-fold-dose (4-fold)/4-fold-equivalent-dose
(eq 4-fold) sgAHs, respectively. The addition of H2-antihista-
mines and/or montelukast significantly decreased the number of
wheals and reduced urticaria activity score for 1 day (UASday)
scores by an average of 1 point within 1 week. H2-antihistamines
and montelukast were used averagely for 16 and 18 weeks,
respectively.
At week 52, 104 patients (61.5%) were in complete remission
(CR) off therapy and 62 (36.7%) in the CR on therapy state
(Table E7, available in this article’s Online Repository at www.
jaci-inpractice.org). Rates of CR off therapy and CR on ther-
apy showed no significant differences among the 3 pairs of
corresponding dose groups (2-fold group vs eq 2-fold group,
4-fold group vs eq 4-fold group, 4-fold plus third-step treatment
group vs eq 4-fold group plus third-step treatment group,
Figure 1). Of the 60 patients completely controlled by first-step
treatments, the percentage of patients with positive serum sIgEs
were significantly greater in the 12 patients in the CR on therapy
state as compared with that in the 48 patients in the CR off
therapy state (66.7% vs 29.2%, P ¼ .022) (Table I). Of the 82
patients completely controlled by second-step treatments,
significantly increased UASday scores and serum levels of CCL17
were associated with the 37 patients in the CR on therapy state as
compared with the 45 patients in the CR off therapy state
(Table I). Of the 22 patients completely controlled by third-step
treatments, significantly longer disease duration was associated
with the 11 patients in the CR on therapy state as compared with
the 11 patients in the CR off therapy state (Table I). The
comparisons of the characteristics of the patients in different
remission states at week 52 of the patients completely controlled
1733
1734 CLINICAL COMMUNICATIONS J ALLERGY CLIN IMMUNOL PRACT
MAY 2020

FIGURE 1. Rates of complete remission (CR) off therapy and CR on therapy at week 52 between the patients completely controlled by 2-
fold and eq 2-fold sgAHs groups, between the patients completely controlled by 4-fold and eq 4-fold sgAHs groups, between the patients
completely controlled by 4-fold sgAHs plus third-step treatment and eq 4-fold sgAHs plus third-step treatment groups. sgAH, Second-
generation H1-antihistamine.

by different folds of sgAHs are described in Table E8 (available
in this article’s Online Repository at www.jaci-inpractice.org).
In this study, based on Cox’s multivariate analysis, UASday
scores > 4 (P ¼ .007; odds ratio [OR], 2.84; 95% confidence
interval [CI], 1.33-6.06) and serum CCL17 levels > 400.8 pg/
mL (P < .001; OR, 8.30; 95% CI, 3.69-18.64) were found to
be independent risk factors for prolonged maintenance therapy
duration of sgAHs.
A total of 15 patients reported adverse effects of sgAHs, and
somnolence was the most common adverse effect in licensed-
dose and 2-fold groups. Somnolence, thirst, gastralgia, and
numbness of hands were observed in 2 patients administering
olopatadine at 4-fold (Table E9, available in this article’s Online
Repository at www.jaci-inpractice.org). Five of 49 were in the
mono-sgAH updosing group, and 4 of 60 in the multi-sgAH
combination group (P ¼ .505). The detailed adverse effects
 VOLUME 8, NUMBER 5
J ALLERGY CLIN IMMUNOL PRACT
TABLE I. Comparison of characteristics of the patients in different remission states at week 52 in the patients completely controlled by first-, second-, and third-step treatment
Patients completely controlled by first-step treatment Patients completely controlled by second-step treatment Patients completely controlled by third-step treatment
Parameters CR off therapy CR on therapy P value CR off therapy CR on therapy P value CR off therapy CR on therapy P value
Number 48 12 45 37 11 11
Age at onset (y), mean  SD 31.7  56.7 49.5  73.3 .673 35.0  13.4 38.1  14.7 .316 36.9  9.2 37.1  14.0 .972
Age at first visit (y), mean  SD 33.8  11.5 36.7  12.1 .448 38.1  13.7 40.2  13.2 .475 38.0  8.5 39.9  12.1 .683
Sex (female/male) 24/24 9/3 .195 28/17 24/13 .822 4/7 8/3 .198
Disease duration (mo), median (IQR) 11 (5.8-36) 4 (3-36) .353 12 (3.3-45) 6 (2-24) .242 2 (1.5-3.3) 12 (2.5-66) .021
Patients with AE, n (%) 16 (9.5) 3 (1.8) .735 5 (3.0) 8 (4.7) .234 5 (3.0) 6 (3.6) .999
History of atopic diseases, n (%) 11 (6.5) 4 (2.4) .472 16 (9.5) 14 (8.3) .999 6 (3.6) 1 (0.6) .063
Urticaria/atopy family history, n (%) 9 (5.3) 4 (2.4) .271 14 (8.3) 12 (7.1) .999 4 (5.8) 5 (3.0) .999
Urticaria family history, n (%) 5 (3.0) 3 (1.8) .191 6 (3.6) 8 (4.7) .384 0 (0) 3 (1.8) .214
Atopy family history, n (%) 4 (2.4) 1 (0.6) .999 8 (4.7) 9 (5.3) .586 4 (2.4) 2 (1.2) .635
UASday mean  SD 4.1  1.1 4.6  0.9 .146 3.9  1.3 4.7  1.3 .007 4.4  1.1 5.2  1.0 .092
tIgE (IU/mL), median (IQR) 137.4 (42.7-221.0) 192.1 (70.9-258.4) .246 93.6 (31.8-139) 111.6 (62.1-246.5) .094 247.9 (107.6-498.2) 144.9 (49.2-228.3) .101
0-100 IU/mL, n (%) 19 (11.2) 3 (1.8) .348 24 (14.2) 16 (9.5) .363 2 (1.2) 5 (3.0) .170
>100 IU/mL, n (%) 29 (17.2) 9 (5.3) 21 (12.4) 21 (12.4) 9 (5.3) 6 (3.6)
CCL17 (pg/mL), mean  SD 245.9  251.1 303.7  151.6 .318 260.0  165.0 426.1  215.0 <.001 470.9  198.7 550.6  279.7 .450
Positive anti-TG/anti-TPO, n (%) 22 (13.0) 3 (1.8) .327 15 (8.9) 14 (8.3) .817 3 (1.8) 4 (2.4) .999
Positive anti-TG, n (%) 19 (11.2) 2 (1.2) .185 13 (7.7) 11 (6.5) .999 3 (1.8) 4 (2.4) .647
Positive anti-TPO, n (%) 10 (5.9) 1 (0.6) .435 6 (3.6) 9 (5.3) .255 1 (0.6) 2 (1.2) .999
Positive serum sIgEs, n (%) 14 (8.3) 8 (4.7) .022 16 (9.5) 17 (10.1) .373 5 (3.0) 2 (1.2) .361

CLINICAL COMMUNICATIONS
AE, Angioedema; CR, complete remission; IQR, interquartile range; SD, standard deviation; sIgE, specific IgE; TG, thyroglobulin; tIgE, total IgE; TPO, thyroid peroxidase; UASday, urticaria activity score for 1 day.
The % expressed as % of the total number of patients (n ¼ 169).
Bold indicates statistical significance (P < .05).

1735
1736 CLINICAL COMMUNICATIONS
are described in this article’s Online Repository at www.jaci-
inpractice.org.
To our knowledge, few studies have been published on the long-
term efficacy and safety of multi-sgAH combination regimens for
CSU. Staevska et al3 reported 27 patients with chronic urticaria
treated with desloratadine at 4-fold for 1 week, whereas the 6 pa-
tients with CIU in Niiyama et al’s study5 were treated with olo-
patadine at 4-fold for 6 weeks. Godse et al4 reported 14 patients
with CSU treated with fexofenadine at 3-fold for 2 weeks; however,
no report has been published using fexofenadine at 4-fold. In this
study, 4-fold doses were used with desloratadine (9 patients,
average duration of 22.1 weeks), olopatadine (6 patients, 23.9
weeks), and fexofenadine (2 patients, 23 weeks). Good tolerance
was observed in these 17 patients. In this study, combinational
regimens of sgAHs at eq 4-fold included 2-sgAH (n ¼ 13) or 3-
sgAH (n ¼ 5) combinations (Table E2, available in this article’s
Online Repository at www.jaci-inpractice.org). The average
treatment durations for the eq 4-fold combination with 2-sgAH
and 3-sgAH were 24.1 and 25.0 weeks, respectively. These 18
patients showed a good tolerance for the long-term eq 4-fold
sgAHs with/without additional third-step medications.
Although a combination of 4-fold sgAHs with H2-antihista-
mines, LRAs, or both has been reported for the treatment of
patients with CIU/CSU, the exact treatment duration was not
described.6 To our knowledge, there are few reports using a
combination of eq 4-fold sgAHs with H2-antihistamines. As H2-
antihistamines and LRAs have extremely low rates of untoward
effects, the American guideline recommends both medications as
second-line treatments.2,7
Curto-Barredo et al8 proposed a baseline UAS7 as the only
predictor for refractoriness to sgAH treatment. Interestingly, we
showed that serum CCL17 levels > 400.8 pg/mL also predicted
longer treatment duration of sgAHs for CSU. CCL17 has been
shown to be a serum biomarker of the disease activity and
severity of CSU.9,10
This study provides preliminary evidence that multi-sgAH
combinations and mono-sgAH updosing regimens show
acceptable long-term efficacy and safety in the treatment of pa-
tients with CSU. H2-antihistamines and montelukast further
enhance the efficacy of combinational and updosing sgAHs
without compromising safety. Overall, although a larger sample
size involving comparative studies will be needed to confirm our
conclusion, our current results provide supportive evidence for
the American guideline.
Acknowledgments
This manuscript was revised for submission in English by the
ED-IT Editorial Service.
a
Department of Dermatology, The First Hospital of China Medical University, Na-
tional Health Commission Key Laboratory of Immunodermatology, Key Labo-
ratory of Immunodermatology of Ministry of Education, Shenyang, China
b
Department of Dermatology, Institute of Dermatology, Chinese Academy of
Medical Science, Nanjing, China
J ALLERGY CLIN IMMUNOL PRACT
MAY 2020
c
Department of Dermatology, West China Hospital, Sichuan University, Chengdu,
China
d
Department of Dermatology, The Third Affiliated Hospital of Sun Yat-Sen Uni-
versity, Guangzhou, China
e
Department of Dermatology, The Second Affiliated Hospital of Harbin Medical
University, Harbin, China
f
Department of Dermatology, The Second Hospital of Jilin University, Changchun,
China
g
Department of Dermatology, Tianjin Medical University General Hospital, Tianjin,
China
h
Department of Dermatology, The Second Xiangya Hospital of Central South
University, Changsha, China
This study was supported by the National Key Clinical Specialist Subject Con-
struction Project on Urticaria from National Health Commission ([2012]649) and
the Basic Research Project from the Educational Department of Liaoning Prov-
ince, China (LZ2015078).
Conflicts of interest: The authors declare that they have no relevant conflicts of
interest.
Received for publication September 6, 2019; revised November 28, 2019; accepted
for publication December 3, 2019.
Available online December 16, 2019.
Corresponding authors: Ting Xiao, MD, PhD, Department of Dermatology, The
First Hospital of China Medical University, National Health Commission Key
Laboratory of Immunodermatology, Key Laboratory of Immunodermatology
of Ministry of Education, No. 155 Nanjing Bei Street, Shenyang 110001,
China. E-mail: cmuxt@126.com; Or: Hongduo Chen, MD, Department of
Dermatology, The First Hospital of China Medical University, National
Health Commission Key Laboratory of Immunodermatology, Key Laboratory
of Immunodermatology of Ministry of Education, No. 155 Nanjing Bei Street,
Shenyang 110001, China. E-mail: hongduochen@hotmail.com.
2213-2198
Ó 2019 American Academy of Allergy, Asthma & Immunology
https://doi.org/10.1016/j.jaip.2019.12.006
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tion, diagnosis and management of urticaria. Allergy 2018;73:1393-414.
2. Bernstein JA, Lang DM, Khan DA, Craig T, Dreyfus D, Hsieh F, et al. The
diagnosis and management of acute and chronic urticaria: 2014 update.
J Allergy Clin Immunol 2014;133:1270-7.
3. Staevska M, Popov TA, Kralimarkova T, Lazarova C, Kraeva S, Popova D,
et al. The effectiveness of levocetirizine and desloratadine in up to 4 times
conventional doses in difficult-to-treat urticaria. J Allergy Clin Immunol 2010;
125:676-82.
4. Godse KV, Nadkarni NJ, Jani G, Ghate S. Fexofenadine in higher doses in
chronic spontaneous urticaria. Indian Dermatol Online J 2010;1:45-6.
5. Niiyama S, Taniguchi T, Tanabe K, Maeda A, Aki R, Mitsui S, et al. A study of
the efficacy of updosing olopatadine hydrochloride for chronic idiopathic urti-
caria [in Japanese]. Prog Med 2010;30:2233-7.
6. Kaplan A, Ledford D, Ashby M, Canvin J, Zazzali JL, Conner E, et al. Oma-
lizumab in patients with symptomatic chronic idiopathic/spontaneous urticaria
despite standard combination therapy. J Allergy Clin Immunol 2013;132:101-9.
7. Wood RA, Khan DA, Lang DM, Fasano MB, Peden DB, Busse PJ, et al.
American Academy of Allergy, Asthma and Immunology response to the
EAACI/GA2LEN/EDF/WAO guideline for the definition, classification, diag-
nosis, and management of urticaria 2017 revision. Allergy 2019;74:411-3.
8. Curto-Barredo L, Archilla LR, Vives GR, Pujol RM, Giménez-Arnau AM.
Clinical features of chronic spontaneous urticaria that predict disease prognosis
and refractoriness to standard treatment. Acta Derm Venereol 2018;98:641-7.
9. Zhang L, Qi R, Yang Y, Gao X, Chen H, Xiao T. Serum miR-125a-5p and
CCL17 upregulated in chronic spontaneous urticaria and correlated with treat-
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10. Lu T, Jiao X, Si M, He P, Zou J, Zhang S, et al. The correlation of serums
CCL11, CCL17, CCL26, and CCL27 and disease severity in patients with ur-
ticaria. Dis Markers 2016;2016:1381760.
J ALLERGY CLIN IMMUNOL PRACT
VOLUME 8, NUMBER 5
ONLINE REPOSITORY
METHODS
Patients
Chronic spontaneous urticaria (CSU) diagnosis was based on
the EAACI/GA2LEN/EDF/WAO guideline.E1 Patients with
inducible urticaria, urticarial vasculitis, and CSU who had been
treated with systemic corticosteroids and/or immunosuppressants
were excluded. Demographic, clinical, and laboratory data were
collected through a structured questionnaire, physical examina-
tions, and laboratory tests as performed on the patients on their
first visit, and an urticaria activity score for 1 day (UASday) was
recorded at this time.
Ethical approval was obtained from institutional ethics com-
mittees, and written consents were obtained from each participant.
Patients aged 18 to 65 years with active CSU were recruited from
June 2014 to July 2017 from 8 medical centers in China.
Early end points
“Control of disease activity” was classified as being in complete
control, partial control, or uncontrolled. Patients with no wheals
or itching were considered as complete control (UASday ¼ 0).
Patients whose symptoms were reduced but not completely ab-
sent were classified as partial control (UASday  1). Patients
whose symptoms did not improve were designated as uncon-
trolled (UASday unchanged or increased).
Late end points
“Remission state” at week 52 was classified as being in com-
plete remission (CR) off therapy or CR on therapy. CR off
therapy was defined as the absence of symptoms for at least 4
weeks in patients not taking any medications. CR on therapy was
defined as the absence of symptoms in patients with therapeutic
medications. CR on minimal therapy was defined as the absence
of symptoms in patients using second-generation H1-antihista-
mines (sgAHs) at licensed doses or less during a dose tapering
procedure.
Treatment regimens
sgAHs administered at licensed doses comprised the first-step
treatment. Multi-sgAH combinations (up to 3 sgAHs, up to a 4-
fold equivalent dose) or mono-sgAH updosing (up to a 4-fold
dose) regimens comprised second-step treatments. If complete
control was not achieved, H2-antihistamines (ranitidine or
famotidine) and montelukast were added sequentially as third-
step treatments. Cyclosporine and tripterygium wilfordii poly-
glycoside (TWP) were used as a fourth-step treatment. TWP is a
Chinese herb belonging to the Celastraceae family with anti-
inflammatory and immunosuppressive effects,E2 in part,
through its ability to inhibit the degranulation of mast cells and
histamine release.E3,E4 As 2 notable adverse effects of TWP
include amenorrhea and oligozoospermia,E5,E6 it is contra-
indicated in patients with CSU with childbearing potential.
TWP is recommended as a third-line treatment by the Chinese
guideline.E7 Omalizumab was not commercially available when
this study was performed. sgAHs produced by both international
and domestic pharmaceutical companies were commercially
available in China. All patients with CSU in this study had been
treated by sgAHs produced by international pharmaceutical
companies. Use of 2-fold updoses included ebastine, bepotastine,
or loratadine, whereas 4-fold updoses consisted of desloratadine,
CLINICAL COMMUNICATIONS 1736.e1
fexofenadine, or olopatadine. Combinations of sgAHs included
loratadine, ebastine, levocetirizine, desloratadine, fexofenadine,
and mizolastine. sgAHs with the potential for prolonging the QT
interval were not allowed to be updosed or combined. If patients
were already on sgAH treatment before presentation, the sgAH
was changed into an international sgAH, or entered into the
treatment steps.
Before complete control was achieved, patients were assessed
weekly and treated with updoses or the addition of combina-
tional medications. If patients experienced any discomfort, the
sgAH being used was replaced with an alternative sgAH. Once
complete control was achieved, the treatment regimen was
continued for at least 2 months. Doses of the sgAHs or other
medications were then tapered every 3 to 4 weeks until all
medications were discontinued.
Laboratory examinations
Serum levels of CCL17 (R&D Systems, Minneapolis, MN)
and total IgE (tIgE) (Euroimmun, Lübeck, Germany) were
determined using ELISA kits. Normal ranges of tIgE were 0 to
100.00 IU/mL.
Serum specific IgEs were determined using immunoblotting
(Euroimmun). Detected allergens included house dust, cat/dog
dander, willow/poplar/elm, ragweed, mugwort, pteronyssinus/
farinae, penicillium/branch spore mold/fumigatus/alternaria,
humulus, cow’s milk, egg white, peanut, soybean, crab, shrimp,
beef, mutton, codfish/lobster/scallop, and salmon/weever/carp. A
test result of  0.7 kU/L was considered positive (levels 2 to 6).
Serum levels of anti-thyroglobulin (TG) and anti-thyroid
peroxidase (TPO) antibodies were determined using a chem-
iluminescence microparticle immunoassay (Abbott Park, Mid-
dletown, DE). Normal ranges of anti-TG and anti-TPO were
0.0000 to 4.1100 IU/mL and 0.0000 to 5.6100 IU/mL,
respectively.
Statistical methods
Data showing a normal distribution were presented as the
mean  standard deviation, whereas data failing to demonstrate a
normal distribution were shown as median and interquartile
range. Prevalence and remission rates were shown as percentages.
Mann-Whitney U-tests and t-tests were used for comparisons
between groups with data that were either lacking or demon-
strating normal distributions, respectively. The c2 and Fisher
exact tests were used for comparing proportions. Prognostic
factors of CR off therapy at week 52 were analyzed using Cox’s
multivariate analysis. In addition, with the use of the receiver
operating characteristic curve, a maximal Youden’s index was
calculated. Youden’s index ¼ sensitivity þ specificity  1.
Youden’s index value is associated with the critical expression
point or the optimal threshold value, also called the cutoff point
for UASday and CCL17. P values less than .05 were required for
results to be considered statistically significant. Statistical analysis
was performed with the use of the IBM SPSS Statistics version
23 and Graphpad 7 programs.
RESULTS
Among the 169 enrolled patients, 130 patients were already
on sgAHs’ treatment before presentation.
1736.e2 CLINICAL COMMUNICATIONS
Control of disease activity
Of the 5 patients who required fourth-step treatment, 3 were
completely controlled with the addition of TWP, whereas the
remaining 2 patients refused cyclosporine or TWP and were
partially controlled. However, of the 3 patients completely
controlled with the addition of TWP, 1 experienced leukocyto-
penia at 4 weeks after the addition of TWP, necessitating the
discontinuation of TWP. She refused cyclosporine and was
partially controlled.
Compared with the 109 patients who were not completely
controlled by sgAHs at licensed doses, there were a significantly
higher percentage of patients aged less than 30 years at disease
onset, a significantly lower prevalence of atopy family history,
and a significantly lower level of serum CCL17 in the 60 patients
who were completely controlled by sgAHs at licensed doses
(Table E3).
Compared with the 142 patients who were completely
controlled by first- and second-step treatments, a significantly
lower disease duration, a significantly higher level of serum
CCL17, a significantly higher percentage of patients with the
serum level of CCL17 over 374.1 pg/mL, and a significantly higher
percentage of angioedema were present in the 22 patients who were
completely controlled by third-step treatment (Table E3).
No significant differences were observed in characteristics of
patients between the 2-fold-dose sgAHs (2-fold) and the 2-fold-
equivalent-dose sgAHs (eq 2-fold) groups, between the 4-fold-
dose sgAHs (4-fold) and the 4-fold-equivalent-dose sgAHs (eq
4-fold) groups, and between the 4-fold plus third-step treatment
and the eq 4-fold plus third-step treatment groups (Table E4).
The scores of UASday were significantly different between the
2-fold complete group (2-fold and eq 2-fold), the 4-fold com-
plete group (4-fold and eq 4-fold), and the step 4 complete group
(Table E5).
In the 22 patients who were completely controlled by third-step
treatment, total glucosides of paeony (TGP) was added after
H2-antihistamines and/or montelukast in 7 patients. However,
UASday scores were not further reduced with the addition of TGP.
TGP is an anti-inflammatory and immunoregulatory Chinese herb
approved for rheumatoid arthritis in ChinaE8-E10 and has been
used off-label for CSU by some dermatologists. The 5
antihistamine-refractory patients who required a fourth-step
treatment presented with significantly prolonged persistent
wheals (>24 hours) and/or significantly higher UASday scores as
compared with the other 164 patients (Table E6).
Remission state at week 52
Of the 56 patients completely controlled by the 2-fold/eq 2-
fold sgAHs, 34 were in the CR off therapy and 22 in the CR
J ALLERGY CLIN IMMUNOL PRACT
MAY 2020
on therapy state. Serum CCL17 levels were significantly
decreased in the CR off therapy group versus the CR on therapy
group (P ¼ .001; Table E8). Of the 18 patients completely
controlled by the 3-fold/eq 3-fold sgAHs, 8 were in the CR off
therapy and 10 in the CR on therapy state. No significant dif-
ferences were observed in characteristics between the CR off
therapy and CR on therapy groups (Table E8). Of the 8 patients
completely controlled by the 4-fold/eq 4-fold sgAHs, 3 were in
the CR off therapy and 5 in the CR on therapy state. No sig-
nificant differences were observed in characteristics between the
CR off therapy and CR on therapy groups (Table E8).
Of the 5 patients requiring a fourth-step treatment, 2 were in
CR on therapy and 3 were not in remission.
Adverse effects
Somnolence was the most common adverse effect of sgAHs,
with other adverse effects including thirst, gastralgia, headache,
diarrhea, and hand numbness (Table E9). Eleven of 139 (7.9%)
patients experienced adverse effects in response to the licensed
dose, whereas 5 of 96 (5.2%) patients to the overlicensed dose
(P ¼ .418). Because of sgAH intolerance, 9 patients required
replacement with other sgAHs. One 59-year-old female patient
reported severe palpitations and persistent tachycardia when she
mistakenly administered 20 mg of ebastine twice daily for a week
while simultaneously taking 20 mg of TWP three times daily.
The cardiac symptoms disappeared after the ebastine was dis-
continued. Only 1 patient self-discontinued ranitidine because of
constipation. A 42-year-old male patient with CSU with no
history of heart disease suffered from palpitations, gastralgia, and
diarrhea in response to a twice daily 10 mg olopatadine regimen.
His adverse effects were relieved at 4 days after discontinuation of
olopatadine (unpublished data). A 4-fold dose of sgAHs could
not be tolerated by all patients with CSU. Updosing procedures
should be performed in a stepwise manner and patients should be
closely monitored. With the appearance of adverse effects, the
responsible sgAH should be discontinued immediately.
LIMITATIONS
Limitations of this study include the lack of UAS7 and
autologous serum skin tests. As the medical system in China
differs from that in Europe and the United States, Chinese pa-
tients often register and can be seen by several different derma-
tologists within the same clinic on the same day. In addition, the
overall compliance of the patients was generally poor, as it was
difficult to persuade them to discontinue use of antihistamines
for 7 days.
J ALLERGY CLIN IMMUNOL PRACT CLINICAL COMMUNICATIONS 1736.e3
VOLUME 8, NUMBER 5

FIGURE E1. Complete control of disease activity in 167 of the 169 patients. The remaining 2 patients refused cyclosporine or trip-
terygium wilfordii polyglycoside (TWP) and were partially controlled. Of the 3 patients completely controlled with the addition of TWP, 1
experienced leukocytopenia at 4 weeks after the addition of TWP, necessitating the discontinuation of TWP. She refused cyclosporine
and was partially controlled.
1736.e4 CLINICAL COMMUNICATIONS J ALLERGY CLIN IMMUNOL PRACT
MAY 2020

TABLE E1. Characteristics of the 169 patients

Parameters
Age at first visit (y), mean  SD 37.5  12.6
Age at onset (y), mean  SD 35.0  13.3
18-20 y, n (%) 23 (13.6)
21-30 y, n (%) 53 (31.4)
31-40 y, n (%) 33 (19.5)
41-50 y, n (%) 33 (19.5)
51-60 y, n (%) 24 (14.2)
61-65 y, n (%) 3 (1.8)
Sex (female/male) 100/69
Female age (y), mean  SD 37.9  12.9
Male age (y), mean  SD 37.0  12.2
Disease duration (mo), median (IQR) 9 (3-36)
6 mo, n (%) 81 (47.9)
7-12 mo, n (%) 23 (13.6)
13-30 mo, n (%) 18 (10.7)
31-60 mo, n (%) 20 (11.8)
>60 mo, n (%) 27 (16.0)
Patients with AE, n (%) 46 (27.2)
History of atopic diseases, n (%) 52 (30.8)
Urticaria/atopy family history, n (%) 49 (29.0)
Urticaria family history, n 25
Atopy family history, n 29
Urticaria and atopy family history, n 5
UASday, mean  SD 4.3  1.3
tIgE (IU/mL), median (IQR) 116.5 (48.2-222.8)
0-100 IU/mL, n (%) 73 (43.2)
>100 IU/mL, n (%) 96 (56.8)
CCL17 (pg/mL), mean  SD 355.7  287.6
Positive anti-TG/anti-TPO, n (%) 63 (37.3)
Positive anti-TG, n (%) 53 (31.4)
Positive anti-TPO, n (%) 31 (18.3)
Positive serum sIgEs, n (%) 63 (37.3)
Follow-up period (wk), mean  SD (range) 102.8  57.8 (52-209.4)

AE, Angioedema; IQR, interquartile range; SD, standard deviation; sIgE, specific
IgE; TG, thyroglobulin; tIgE, total IgE; TPO, thyroid peroxidase; UASday, urticaria
activity score for 1 day.
The % expressed as % of the total number of patients (n ¼ 169).
J ALLERGY CLIN IMMUNOL PRACT
VOLUME 8, NUMBER 5
TABLE E2. Treatment regimens of the 169 patients
Dosage
Licensed dose sgAHs
2-fold dose sgAHs
2-fold equivalent dose sgAHs
3-fold dose sgAHs
3-fold equivalent dose sgAHs
4-fold dose sgAHs
4-fold equivalent dose sgAHs
4-fold dose sgAHs and H2-
antihistamines
4-fold dose sgAHs and H2-
antihistamines and TGP
4-fold dose sgAHs and
H2-antihistamines and
montelukast
4-fold dose sgAHs and H2-
antihistamines and
montelukast and TGP
4-fold equivalent dose sgAHs
and H2-antihistamines
4-fold equivalent dose sgAHs
and H2-antihistamines and
TGP
4-fold equivalent dose sgAHs
and H2-antihistamines and
montelukast
4-fold equivalent dose sgAHs
and montelukast
4-fold dose sgAHs and TWP
4-fold equivalent dose sgAHs
and TWP
sgAH, Second-generation H1-antihistamine; TGP, total glucosides of paeony; TWP, tripterygium wilfordii polyglycoside.
CLINICAL COMMUNICATIONS 1736.e5
n Treatment regimens
60 Ebastine 10 mg once daily, n ¼ 28; loratadine 10 mg once daily, n ¼ 17; desloratadine 5 mg once daily,
n ¼ 6; mizolastine 10 mg once daily, n ¼ 4; fexofenadine 180 mg once daily, n ¼ 3; bepotastine 10 mg
once daily, n ¼ 1; levocetirizine 5 mg once daily, n ¼ 1
31 Ebastine 20 mg once daily, n ¼ 20; bepotastine 10 mg twice daily, n ¼ 7; olopatadine 5 mg twice daily,
n ¼ 2; loratadine 10 mg twice daily, n ¼ 1; fexofenadine 180 mg twice daily, n ¼ 1
25 Loratadine 10 mg, ebastine 10 mg once daily, n ¼ 10; loratadine 10 mg, levocetirizine 5 mg once daily,
n ¼ 5; loratadine 10 mg, desloratadine 5 mg once daily, n ¼ 4; loratadine 10 mg, fexofenadine 180 mg
once daily, n ¼ 3; desloratadine 5 mg, ebastine 10 mg once daily, n ¼ 1; ebastine 10 mg, levocetirizine
5 mg once daily, n ¼ 1; mizolastine 10 mg, levocetirizine 5 mg once daily, n ¼ 1
1 Olopatadine 5 mg three times daily, n ¼ 1
17 Ebastine 20 mg, fexofenadine 180 mg once daily, n ¼ 9; ebastine 20 mg, loratadine 10 mg once daily,
n ¼ 2; ebastine 20 mg, levocetirizine 5 mg once daily, n ¼ 2; bepotastine 10 mg twice daily and
levocetirizine 5 mg once daily, n ¼ 2; desloratadine 5 mg, loratadine 10 mg, fexofenadine 180 mg once
daily, n ¼ 1; fexofenadine 180 mg twice daily and levocetirizine 5 mg once daily, n ¼ 1
3 Desloratadine 10 mg twice daily, n ¼ 2; olopatadine 10 mg twice daily, n ¼ 1
5 Ebastine 20 mg once daily, olopatadine 5 mg twice daily, n ¼ 3; fexofenadine 180 mg, olopatadine 5 mg
twice daily, n ¼ 1; desloratadine 5 mg, loratadine 10 mg, ebastine 20 mg once daily, n ¼ 1
2 Desloratadine 10 mg, ranitidine 350 mg twice daily, n ¼ 2
3 Desloratadine 10 mg, ranitidine 350 mg twice daily, TGP 2 capsules three times daily, n ¼ 1; olopatadine
10 mg, ranitidine 350 mg twice daily, TGP 2 capsules three times daily, n ¼ 2
4 Desloratadine 10 mg twice daily, montelukast 10 mg once daily, ranitidine 350 mg twice daily, n ¼ 1;
fexofenadine 240 mg three times daily, montelukast 10 mg once daily, ranitidine 350 mg twice daily,
n ¼ 1; olopatadine 10 mg twice daily, montelukast 10 mg once daily, ranitidine 350 mg twice daily,
n ¼ 1; desloratadine 10 mg twice daily, montelukast 10 mg once daily, famotidine 20 mg twice daily,
n¼1
3 Desloratadine 10 mg twice daily, montelukast 10 mg once daily, famotidine 20 mg twice daily, TGP 2
capsules three times daily, n ¼ 1; olopatadine 10 mg twice daily, montelukast 10 mg once daily,
famotidine 20 mg twice daily, TGP 2 capsules three times daily, n ¼ 1; desloratadine 10 mg twice daily,
montelukast 10 mg once daily, ranitidine 350 mg twice daily, TGP 2 capsules three times daily, n ¼ 1
3 Fexofenadine 120 mg three times daily, olopatadine 5 mg, ranitidine 350 mg twice daily, n ¼ 2; ebastine
20 mg, fexofenadine 180 mg, loratadine 10 mg once daily, ranitidine 350 mg twice daily, n ¼ 1
1 Ebastine 20 mg once daily, olopatadine 5 mg, famotidine 20 mg twice daily, TGP 2 capsules three times
daily, n ¼ 1
5 Ebastine 20 mg once daily, olopatadine 5 mg twice daily, montelukast 10 mg once daily, famotidine 20
mg twice daily, n ¼ 4; ebastine 20 mg, fexofenadine 180 mg, loratadine 10 mg, montelukast 10 mg
once daily, ranitidine 350 mg twice daily, n ¼ 1
3 Desloratadine 5 mg twice daily, ebastine 20 mg once daily, montelukast 10 mg once daily, n ¼ 1; ebastine
20 mg once daily, olopatadine 5 mg twice daily, montelukast 10 mg once daily, n ¼ 1; ebastine 20 mg,
fexofenadine 180 mg, loratadine 10 mg, montelukast 10 mg once daily, n ¼ 1
2 Olopatadine 10 mg twice daily, TWP 20 mg three times daily, n ¼ 1; fexofenadine 240 mg three times
daily, TWP 20 mg three times daily, n ¼ 1
1 Ebastine 20 mg, desloratadine 5 mg, loratadine 10 mg once daily, TWP 20 mg three times daily, n ¼ 1
1736.e6 CLINICAL COMMUNICATIONS J ALLERGY CLIN IMMUNOL PRACT
MAY 2020

TABLE E3. Characteristics of the 60 patients completely controlled by first-step treatment and the 22 patients completely controlled by
third-step treatment
Patients completely Patients not Patients completely Patients completely
controlled by completely controlled controlled by controlled by first- and
Parameters licensed-dose sgAHs by licensed-dose sgAHs P value third-step treatment second-step treatment P value
Number 60 109 22 142
Age at onset (y), mean  SD 31.6  12.4 36.8  13.5 .015 37.0  11.6 34.4  13.5 .390
Age at first visit (y), mean  SD 34.4  11.6 39.2  12.8 .016 38.9  10.2 37.1  12.9 .520
Sex (female/male) 33/27 67/42 .419 12/10 85/57 .648
Disease duration (mo), median (IQR) 10 (4-36) 9 (2-36) .326 3 (2-36) 12 (3-36) .046
Patients with AE, n (%) 19 (11.2) 27 (16.0) .369 11 (6.5) 32 (18.9) .016
History of atopic diseases, n (%) 15 (8.9) 37 (21.9) .296 7 (4.1) 45 (26.6) .999
Urticaria/atopy family history, n (%) 13 (7.7) 36 (21.3) .156 9 (5.3) 39 (23.1) .214
Urticaria family history, n (%) 8 (4.7) 17 (10.1) .822 3 (1.8) 22 (13.0) .999
Atopy family history, n (%) 5 (3.0) 24 (14.2) .032 6 (3.6) 22 (13.0) .219
UASday, mean  SD 4.2  1.1 4.4  1.3 .157 4.8  1.1 4.2  1.3 .066
tIgE (IU/mL), median (IQR) 146.9 (46.6-248.9) 107.5 (48.7-200.2) .489 163.8 (76.8-404.8) 115.9 (45.4-208.9) .069
0-100 IU/mL, n (%) 22 (13.0) 51 (30.2) .204 7 (4.1) 62 (36.7) .295
>100 IU/mL, n (%) 38 (22.5) 58 (34.3) 15 (8.9) 80 (47.3)
CCL17 (pg/mL), mean  SD 257.5  234.6 409.7  300.4 <.001 510.8  240.3 302.2  220.9 <.001
280.1 pg/mL, n (%) 38 (22.5) 41 (24.3) .002 e e e
>374.1 pg/mL, n (%) e e e 17 (10.1) 39 (23.1) <.001
Positive anti-TG/anti-TPO, n (%) 25 (14.8) 38 (22.5) .409 7 (4.1) 54 (32.0) .642
Positive anti-TG, n (%) 21 (12.4) 32 (18.9) .490 7 (4.1) 45 (26.6) .999
Positive anti-TPO, n (%) 11 (6.5) 20 (11.8) .999 3 (1.8) 26 (15.4) .768
Positive serum sIgEs, n (%) 22 (13.0) 41 (24.3) .519 7 (4.1) 55 (32.5) .640

AE, Angioedema; IQR, interquartile range; SD, standard deviation; sgAH, second-generation H1-antihistamine; sIgE, specific IgE; TG, thyroglobulin; tIgE, total IgE; TPO,
thyroid peroxidase; UASday, urticaria activity score for 1 day.
The % expressed as % of the total number of patients (n ¼ 169).
 VOLUME 8, NUMBER 5
J ALLERGY CLIN IMMUNOL PRACT
TABLE E4. Comparisons of characteristics between the patients completely controlled by sgAHs at 2-fold and eq 2-fold, sgAHs at 4-fold and eq 4-fold, and sgAHs at 4-fold plus third-step
treatment and eq 4-fold plus third-step treatment
4-fold sgAHs eq 4-fold sgAHs
eq 2-fold 4-fold eq 4-fold plus third-step plus third-step
Parameters 2-fold sgAHs sgAHs P value sgAHs sgAHs P value treatment treatment P value
Number 31 25 3 5 11 11
Age at first visit (y), mean  SD 36.2  14.4 42.7  13.6 .094 31.1  5.6 37.7  14.1 .475 36.6  9.3 41.2  11.1 .305
Sex (female/male) 23/8 15/10 .388 1/2 2/3 .999 6/5 6/5 .999
Disease duration (mo), median (IQR) 6 (2-36) 12 (4-36) .453 17 (3-18) 2 (1.5-3) .071 3.5 (2-57) 2 (1.8-10.5) .429
Patients with AE, n (%) 7 (4.1) 2 (1.2) .167 0 (0) 0 (0) .999 5 (3.0) 6 (3.6) .999
History of atopic diseases, n (%) 15 (8.9) 6 (3.6) .095 1 (0.6) 3 (1.8) .999 5 (3.0) 2 (1.2) .361
Urticaria/atopy family history, n (%) 6 (3.6) 5 (3.0) .999 1 (0.6) 3 (1.8) .999 5 (3.0) 4 (2.4) .999
Urticaria family history, n (%) 2 (1.2) 4 (2.4) .391 1 (0.6) 1 (0.6) .999 1 (0.6) 2 (1.2) .999
Atopy family history, n (%) 4 (2.4) 2 (1.2) .682 1 (0.6) 3 (1.8) .999 4 (2.4) 2 (1.2) .635
UASday, mean  SD 4.3  1.3 3.6  1.4 .063 5.0  1.0 5.4  0.5 .482 5.0  1.1 4.5  1.2 .373
tIgE (IU/mL), median (IQR) 86.8 (30.5-148.2) 68.9 (42.4-195.9) .731 429.3 (107.5-1169) 106.8 (50.9-222.8) .143 157.5 (70.9-390.8) 170.1 (78.8-498.2) .949
0-100 IU/mL, n (%) 18 (10.7) 14 (8.3) .877 0 (0) 2 (1.2) .999 4 (2.4) 4 (2.4) .999
>100 IU/mL, n (%) 13 (7.7) 11 (6.5) 3 (1.8) 4 (2.4) 7 (4.1) 7 (4.1)
CCL17 (pg/mL), mean  SD 298.4  151.9 247.1  156.3 .220 351.9  299.4 395.4  221.7 .820 447.1  198.5 574.5  269.9 .222
Positive anti-TG/anti-TPO, n (%) 12 (7.1) 8 (4.7) .780 0 (0) 2 (1.2) .464 3 (1.8) 4 (2.4) .999

CLINICAL COMMUNICATIONS
Positive anti-TG, n (%) 8 (4.7) 7 (4.1) .999 0 (0) 2 (1.2) .464 3 (1.8) 4 (2.4) .999
Positive anti-TPO, n (%) 8 (4.7) 3 (1.8) .312 0 (0) 2 (1.2) .464 1 (0.6) 2 (1.2) .999
Positive serum sIgEs, n (%) 9 (5.3) 13 (7.7) .103 1 (0.6) 2 (1.2) .999 5 (3.0) 2 (1.2) .361
2-fold, 2-Fold-dose; AE, angioedema; eq 2-fold, 2-fold-equivalent-dose; IQR, interquartile range; SD, standard deviation; sgAH, second-generation H1-antihistamine; sIgE, specific IgE; TG, thyroglobulin; tIgE, total IgE; TPO, thyroid
peroxidase; UASday, urticaria activity score for 1 day.
The % expressed as % of the total number of patients (n ¼ 169).

1736.e7
1736.e8 CLINICAL COMMUNICATIONS J ALLERGY CLIN IMMUNOL PRACT
MAY 2020

TABLE E5. The characteristics between the 2-fold complete group, the 4-fold complete group, and the step 4 complete group
2-fold complete 4-fold complete Step 4 complete P value P value P value
Parameters groupa groupb groupc (a vs b) (a vs c) (b vs c)
Number 56 8 3
Age at onset (y), mean (SD) 36.7 (14.6) 32.8 (13.6) 45.7 (13.7) 478 .301 .195
Age at first visit (y), mean (SD) 39.1 (14.2) 35.2 (11.6) 47.4 (14.0) .471 .330 .177
Sex (female/male) 38/18 3/5 3/0 .124 .546 .182
Disease duration (mo), median (IQR) 12 (3-36) 2.5 (2-14) 18 (13-36) .031 .463 .049
Patients with AE, n (%) 9 (5.3) 0 (0) 2 (1.2) .587 .086 .055
History of atopic diseases, n (%) 21 (12.4) 4 (2.4) 0 (0) .701 .546 .236
Urticaria/atopy family history, n (%) 11 (6.5) 4 (2.4) 1 (0.6) .079 .501 .999
Urticaria family history, n (%) 6 (3.6) 2 (1.2) 0 (0) .260 .999 .999
Atopy family history, n (%) 6 (3.6) 4 (2.4) 1 (0.6) .016 .320 .999
UASday mean (SD) 4.0 (1.4) 5.3 (0.7) 6 (0) .001 <.001 .020
Total IgE (IU/mL), median (IQR) 80.3 (38.7-170.4) 110.5 (103-404.5) 3.6 (2.7-140.2) .161 .183 .376
0-100 IU/mL, n (%) 32 (18.9) 1 (0.6) 2 (1.2) .025 .999 .151
>100 IU/mL, n (%) 24 (14.2) 7 (4.1) 1 (0.6)
CCL17 (pg/mL), mean (SD) 275.5 (154.6) 379.1 (223.8) 1469.6 (618.9) .103 .079 .086
Positive anti-TG/anti-TPO, n (%) 20 (11.8) 2 (1.2) 1 (0.6) .704 .999 .999
Positive serum specific IgEs, n (%) 22 (13.0) 3 (1.8) 0 (0) .999 .286 .491

AE, Angioedema; IQR, interquartile range; SD, standard deviation; sgAH, second-generation H1-antihistamine; sIgE, specific IgE; TG, thyroglobulin; tIgE, total IgE; TPO,
thyroid peroxidase; UASday, urticaria activity score for 1 day.
The % expressed as % of the total number of patients (n ¼ 169). a, the 56 patients who were completely controlled by sgAHs at 2-fold dose or 2-fold equivalent dose; b, the 8
patients who were completely controlled by sgAHs at 4-fold dose or 4-fold equivalent dose; c, the 3 patients who were completely controlled by fourth-step treatment.

TABLE E6. Characteristics of the 5 patients who required fourth-step treatment

CCL17 Anti-TG/anti-TPO
Case Age Sex UASday (pg/mL) antibodies Therapeutic regimens Control of disease
1 32 F 6 1619.3 Anti-TPO þ Olopatadine 10 mg twice daily, TWP 20 Complete control
mg three times daily
2* 51 F 6 1999.9 Negative Fexofenadine 240 mg three times daily, Complete control, then partial
TWP 20 mg three times daily control
3 59 F 6 789.7 Negative Ebastine 20 mg, desloratadine 5 mg, Complete control
loratadine 10 mg once daily, TWP 20
mg three times daily
4 51 M 5 659.8 Anti-TG þ, anti-TPO þ Desloratadine 10 mg twice daily, Partial control
montelukast 10 mg once daily,
ranitidine 350 mg twice daily
5 27 M 6 890.7 Negative Fexofenadine 120 mg three times daily, Partial control
olopatadine 5 mg, ranitidine 350 mg
twice daily

TG, Thyroglobulin; TPO, thyroid peroxidase; TWP, tripterygium wilfordii polyglycoside; UASday, urticaria activity score for 1 day.
*Case 2 experienced leukocytopenia 4 weeks after the addition of TWP and discontinued TWP. She refused cyclosporine and was partially controlled.
J ALLERGY CLIN IMMUNOL PRACT CLINICAL COMMUNICATIONS 1736.e9
VOLUME 8, NUMBER 5

TABLE E7. The remission states of the 169 patients at week 52

CR on therapy
CR on minimal CR on overlicensed-dose
Treatment regimens CR off therapy therapy sgAH therapy Symptomatic
Number 104 50 12 3
Licensed-dose (n/N) 48/60 12/60 0/60 0/60
2-fold and eq 2-fold (n/N) 34/56 20/56 2/56 0/56
2-fold (n/N) 19/31 12/31 0/31 0/31
eq 2-fold (n/N) 15/25 8/25 2/25 0/25
3-fold and eq 3-fold (n/N) 8/18 9/18 1/18 0/18
3-fold (n/N) 0/1 1/1 0/1 0/1
eq 3-fold (n/N) 8/17 8/17 1/17 0/17
4-fold and eq 4-fold (n/N) 3/8 3/8 2/8 0/8
4-fold (n/N) 1/3 1/3 1/3 0/3
eq 4-fold (n/N) 2/5 2/5 1/5 0/5
4-fold and eq 4-fold with third-step medications (n/N) 11/22 6/22 5/22 0/22
4-fold þ third-step medications (n/N) 6/11 3/11 2/11 0/11
eq 4-fold þ third-step medications (n/N) 5/11 3/11 3/11 0/11
4-fold and eq 4-fold þTWP (n/N) 0/3 0/3 2/3 1/3
4-foldþTWP (n/N) 0/2 0/2 1/2 1*/2
eq 4-fold þTWP (n/N) 0/1 0/1 1/1 0/1
Refused addition with cyclosporine/TWP (n/N) 0/2 0/2 0/2 2/2
The third-step medications included H2-antihistamines (ranitidine or famotidine), montelukast, and total glucosides of paeony.
2-fold, 2-Fold-dose; CR, complete remission; eq 2-fold, 2-fold-equivalent-dose; sgAH, second-generation H1-antihistamine; TWP, tripterygium wilfordii polyglycoside.
*One patient experienced leukocytopenia 4 weeks after the addition of TWP and discontinued TWP. She refused cyclosporine and was symptomatic.
 1736.e10
CLINICAL COMMUNICATIONS
TABLE E8. Comparison of characteristics of the patients in different remission states in the patients completely controlled by sgAHs at 2-fold or eq 2-fold, sgAHs at 3-fold or eq 3-fold, and
sgAHs at 4-fold or eq 4-fold
2-fold/eq 2-fold 3-fold/eq 3-fold 4-fold/eq 4-fold
Parameters CR off therapy CR on therapy P value CR off therapy CR on therapy P value CR off therapy CR on therapy P value
Number 34 22 8 10 3 5
Age at onset (y), mean  SD 34.9  13.6 39.4  16.0 .268 37.5  14.9 36.9  11.4 .924 29.0  7.8 36.2  15.1 .476
Age at first visit (y), mean  SD 37.7  14.1 41.2  14.7 .382 42.6  13.5 38.9  10.9 .526 29.6  7.7 38.6  13.0 .199
Sex (female/male) 22/12 16/6 .573 5/3 6/4 .999 1/2 2/3 .999
Disease duration (mo), median (IQR) 12 (3.8-39) 6 (2.5-24) .353 12 (4-156) 10 (2.5-94) .457 2 (1.5-18) 3 (2-10.5) .786
Patients with AE, n (%) 4 (2.4) 5 (3.0) .294 1 (0.6) 3 (1.8) .588 0 (0) 0 (0) .999
History of atopic diseases, n (%) 13 (7.7) 8 (4.7) .999 1 (0.6) 4 (2.4) .314 2 (1.2) 2 (1.2) .999
Urticaria/atopy family history, n (%) 8 (4.7) 3 (1.8) .498 4 (2.4) 7 (4.1) .630 2 (1.2) 2 (1.2) .999
Urticaria family history, n (%) 4 (2.4) 2 (1.2) .999 2 (1.2) 4 (2.4) .638 0 (0) 2 (1.2) .464
Atopy family history, n (%) 4 (2.4) 2 (1.2) .999 2 (1.2) 5 (3.0) .367 2 (1.2) 2 (1.2) .999
UASday mean  SD 3.7  1.3 4.4  1.4 .061 4.4  1.3 5.1  1.0 .255 5.0  1.0 5.4  0.5 .516
tIgE (IU/mL), median (IQR) 92.0 (39.0-155.0) 66.2 (35.7-179.3) .671 81.9 (17.4-138.6) 91.9 (26.4-174) .294 107.5 (0-115.5) 330.1 (104.3-799.2) .393
0-100 IU/mL, n (%) 18 (10.7) 14 (8.3) .430 5 (3.0) 2 (1.2) .066 1 (0.6) 0 (0) .375
>100 IU/mL, n (%) 16 (9.5) 8 (4.7) 3 (1.8) 8 (4.7) 1 (0.6) 5 (3.0)
CCL17 (pg/mL), mean  SD 217.8  109.6 364.7  173.2 .001 403.7  234.3 577.3  236.7 .140 354.6  286.3 393.8  230.6 .774
Positive anti-TG/anti-TPO, n (%) 10 (5.9) 10 (5.9) .262 5 (3.0) 2 (1.2) .145 0 (0) 2 (1.2) .464
Positive anti-TG, n (%) 8 (4.7) 7 (4.1) .547 5 (3.0) 2 (1.2) .145 0 (0) 2 (1.2) .464
Positive anti-TPO, n (%) 5 (3.0) 6 (3.6) .310 1 (0.6) 1 (0.6) .999 0 (0) 2 (1.2) .464
Positive serum sIgEs, n (%) 13 (7.7) 9 (5.3) .999 2 (1.2) 6 (3.6) .188 1 (0.6) 2 (1.2) .999

2-fold, 2-Fold-dose; AE, angioedema; CR, complete remission; eq 2-fold, 2-fold-equivalent-dose; IQR, interquartile range; SD, standard deviation; sgAH, second-generation H1-antihistamine; sIgE, specific IgE; TG, thyroglobulin; tIgE, total
IgE; TPO, thyroid peroxidase; UASday, urticaria activity score for 1 day.
The % expressed as % of the total number of patients (n ¼ 169).

J ALLERGY CLIN IMMUNOL PRACT

MAY 2020
J ALLERGY CLIN IMMUNOL PRACT CLINICAL COMMUNICATIONS 1736.e11
VOLUME 8, NUMBER 5

TABLE E9. The adverse effects of second-generation H1-antihistamines (sgAHs)

Number sgAHs Dose Frequency Adverse effects Alternative sgAHs
6 Loratadine Licensed dose 6/48 Slight somnolence
1 Loratadine Licensed dose, 2-fold dose 1/48 Somnolence, headache, diarrhea Ebastine, olopatadine
Fexofenadine 1/6
1 Fexofenadine Licensed dose 1/20 Headache Loratadine
1 Ebastine Licensed dose 1/41 Somnolence Mizolastine
1 Ebastine 2-fold dose 1/49 Somnolence Bepotastine
1 Levocetirizine Licensed dose 1/14 Somnolence Bepotastine
1 Olopatadine 2-fold dose 1/15 Somnolence Fexofenadine
1 Olopatadine 4-fold dose 1/8 Somnolence, thirst, gastralgia Desloratadine
1 Olopatadine 4-fold dose 1/8 Numbness of hands Olopatadine 2-fold dose, ebastine
1 Bepotastine Licensed dose 1/2 Somnolence Desloratadine

Frequency means the number of patients who reported adverse effects of a certain sgAH in the total number of patients who used the same sgAH.

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