Journal of Dermatological Treatment

ISSN: 0954-6634 (Print) 1471-1753 (Online) Journal homepage: https://www.tandfonline.com/loi/ijdt20

Efficacy and Safety of Active Vitamin D

Supplementation in Chronic Spontaneous
Urticaria Patients

Amal Ahmed Mohamed, Maha S. Hussein, Eman Mohamed Salah, Ahmed

eldemery, Mona Mohamed Darwish, Doaa M. Ghaith, Rasha A Attala &
Radwa El borolossy

To cite this article: Amal Ahmed Mohamed, Maha S. Hussein, Eman Mohamed Salah, Ahmed
eldemery, Mona Mohamed Darwish, Doaa M. Ghaith, Rasha A Attala & Radwa El borolossy
(2020): Efficacy and Safety of Active Vitamin D Supplementation in Chronic Spontaneous Urticaria
Patients, Journal of Dermatological Treatment, DOI: 10.1080/09546634.2020.1762838

To link to this article: https://doi.org/10.1080/09546634.2020.1762838

Accepted author version posted online: 29

Apr 2020.

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Informative title: "Efficacy and Safety of Active Vitamin D
Supplementation in Chronic Spontaneous Urticaria Patients"

Running title: Active vitamin D and Chronic Spontaneous Urticaria

Article type: Original Research
I. AUTHORS NAMES AND AFFILIATIONS

Amal Ahmed Mohamed, MD 1, Maha S. Hussein, MD 2, Eman Mohamed Salah, MD

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, Ahmed eldemery, MD 4, Mona Mohamed Darwish, MD 5, Doaa M. Ghaith, MD6

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,Rasha A Attala, MD7, Radwa El borolossy, PhD8

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1
Department of Biochemistry, National Hepatology and Tropical Medicine Research
Institute Egypt.
2
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Department of Dermatology and Andrology, National research Centre
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3
Department of Dermatology, Andrology, Sexual Medicine and STDs, Faculty of
medicine, Helwan University, Cairo, Egypt.
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4
Medical Biochemistry, Faculty of medicine OCTOBER 6 UNIVERSITY
5
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Department of Dermatology, EL Sahel teaching hospital

6
Clinical and Chemical Pathology Department, Faculty of Medicine, Cairo University,
Egypt
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7
Department of Dermatology, National Hepatology and Tropical Medicine Research
Institute Egypt
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8
Department of Clinical Pharmacy, Faculty of Pharmacy Ain Shams University,
Cairo, Egypt.
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II. CORRESPONDING AUTHOR:
Name: Radwa Maher EL Borolossy
Address: 6 street 182, Gesr el Suez, Cairo, Egypt
Mail: Radwa.maher14 @yahoo.com
Mobile: +201227052880
III. AUTHOR FOR REPRINTS
Name: Radwa Maher EL Borolossy
Address: 6 street 182, Gesr el Suez, Cairo, Egypt
Mail: Radwa.maher14 @yahoo.com

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Mobile: +201227052880

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DISCLOSURE OF FUNDING: No source of funding from any organization

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CONFLICT OF INTEREST: None
Text word count: 2304
Number of references: 31
Number of tables: 3
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Number of Figures: 4
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Efficacy and Safety of Active Vitamin D Supplementation in Chronic
Spontaneous Urticaria Patients
Abstract
Background: Chronic spontaneous urticaria (CSU) is a common skin disorder

affecting negatively patients' lives. Vitamin D deficiency has been reported to be

associated to many allergic skin disorders. Objective: This study aimed to evaluate

the association between the serum level of 25 hydroxy vitamin D and CSU and to

assess the efficacy and safety of active vitamin D in management of CSU.

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Methods: The study was conducted on 77 patients with CSU and 67 healthy controls,

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then the 77 CSU patients were randomized to either the study group that received

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0.25ug alfacalcidol daily or the placebo group that received oral placebo for 12

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weeks. Results: Serum 25(OH) D was significantly lower in CSU as compared to

healthy controls and was negatively correlated to the urticarial severity. After
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alfacalcidol administration, the study group showed significant higher level of
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25(OH) D compared to placebo group. In addition, mean serum level of IL6, hsCRP

and TNFα significantly decreased in the study group in comparison to placebo group
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and as compared to their baseline results. Conclusion: Vitamin D deficiency is more

common in CSU patients as compared to healthy people and hence, alfacalcidol might
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have a beneficial role as add on therapy in CSU management with no reported side
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effects.
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Key words: Chronic Spontaneous urticaria- Active Vitamin D- Interleukin 6-

Tumor necrosis factor alpha.

Introduction
Chronic spontaneous urticaria (CSU) is one of the most common cutaneous disorder,

characterized by transient pruritic swellings of the skin (wheal or hive) in the

uppermost superficial dermal layer in different locations of body that occur in the

absence of an identifiable trigger affecting the patients for more than 6 weeks at least

2 times a week (1). In 50% of the occasions, angioedema (swelling of deep

subcutaneous tissues) may accompany the hives (2).

The pathophysiology of CSU is not well-understood, but it may involve the

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dysregulation of intracellular signaling pathways within mast cells and basophils that

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lead to defects in trafficking or function of these cells (3). Moreover, it involves the

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development of autoantibodies to immunoglobulin E (IgE) on both mast cells and

basophils (4).
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In addition, increased levels of circulating pro-inflammatory cytokines, such as tumor
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necrosis factor-α, interleukin (IL)-1, IL-6, and IL-12 have been observed in patients

with CSU. Moreover, an elevated level of IL-6 is significantly associated with the
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clinical severity of CSU. Therefore, it is supposed that cytokines and chemokines are
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contributing to the skin lesions observed in CSU (5).

Second-generation H1-antihistamines are recommended as the first-line treatment for

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most patients, for refractory patients, a short course of systemic corticosteroids,

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omalizumab or cyclosporine is recommended (6).

Vitamin D is a fat-soluble vitamin, exists in two forms: D2 (ergocalciferol) and D3

(Cholecalciferol) (7). Vitamins D2 and D3 from diets and vitamin D3 from skin

photobiosynthesis are initially metabolized by the liver enzyme 25-hydroxylase to 25-

hydroxyvitamin D (25(OH) D), the major circulating metabolite which is then

metabolized in the kidneys by the enzyme 1α-hydroxylase to 1, 25-dihydroxyvitamin

D (1, 25(OH) 2D), the most biologically active form of vitamin D (8).

Although Vitamin D is well known by its main role in the bone homeostasis, it also

can perform several immunomodulatory actions in both innate and adaptive immunity

primarily by affecting its nuclear (nVDR) and plasma membrane receptors (mVDR)

on epithelial cells, mast cells, monocytes, macrophages, T-cells, B-cells, and dendritic

cells (9). The role of vitamin D in various chronic diseases such as malignancies,

infectious diseases, autoimmune diseases and allergic disease, including atopic

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dermatitis and asthma, has been a matter of great interest (10).

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Some studies have shown that vitamin D is involved in the pathogenesis of CSU (11-

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13), while other studies have demonstrated clinical improvement in CSU with vitamin

D supplements (14-16). However, there are a limited number of randomized

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controlled studies on this issue, and their results are inconsistent. Therefore, further
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studies are required to evaluate the vitamin D role in development of CSU and its

potential therapeutic efficacy.

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Hence, the primary aim of this study was to evaluate the vitamin D role in
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development of CSU by comparing the serum level of 25- hydroxy- vitamin D in

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CSU patients and healthy controls and to assess the correlation between the disease

severity and vitamin D deficiency. The secondary objective was to evaluate the effect
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of active vitamin D supplementation on serum vitamin D replenishment, and to detect

its efficacy and safety as an add on therapy to CSU management in a clinical setting

and according of our knowledge this is the first clinical trial to assess this objective.
Patients and methods:
This study was prospective, randomized, controlled and single blinded clinical trial. It

was conducted on 77 patients with CSU diagnosis recruited from Outpatient

Dermatology Clinic of National Hepatology and Tropical Medicine Research

Institute (NHTMRI), Cairo, Egypt, over a period of 12 months from November 2016

to November 2017. Sixty-seven age and sex matched healthy controls were also

enrolled to compare serum 25- hydroxy- vitamin D as an index of vitamin D content

between CSU patients and healthy individual as an index of vitamin D content.

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The sample size was calculated based on a confidence interval of 95%, an alpha value

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of 5%, and a worldwide prevalence of vitamin D deficiency of around 2%. This

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resulted in a required sample size of 50 cases and 50 controls.

Then the 77 CSU patients were simply randomized into 2 groups:

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Group 1 (Study group): 38 patients received 0.25ug alfacalcidol once daily for 12
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weeks in addition to the standard therapy (Hydroxyzine 25 mg/day)

Group 2 (Placebo group): 39 patients received an oral placebo taken with the same
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regimen for 12 weeks in addition to the standard therapy (Hydroxyzine 25 mg/day)

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Inclusion Criteria: Adults >18 years of age, having urticaria episodes at least 2 days
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per week for 6 weeks or longer with/without angioedema.

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Exclusion Criteria: Patients with only physical urticaria, urticarial vasculitis,

hereditary or acquired angioedema. Patients with dyslipidemia, diabetes,

hypertension, pre-existing cardiovascular disease, cerebro-vascular accidents,

hypothyroidism, smokers, and other systemic or cutaneous disorders including atopic

dermatitis, psoriasis etc. Patients with hypercalcemia (>11 mg/dL), diabetes, renal

insufficiency, hepatic disorders, hyperparathyroidism, sarcoidosis, other

granulomatous disorders, malignancy. Pregnant and lactating women and patients

who have taken Vitamin D supplementation in past 6 months.

Alfacalcidol (One Alpha®) soft gelatin capsule was manufactured by LEO Company

for pharmaceutical and chemical industries, Denmark. The placebo was manufactured

and supplied by Memphis Company for pharmaceutical and chemical industries,

Cairo, Egypt.

The following data was collected for both CSU patients and healthy controls;

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Demographic data: including age, sex and body mass index (BMI), smoking history,

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family history.

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For only the CSU patients; the history of CSU including: age of onset, duration, and

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history of present and previous therapy were documented.
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Dermatological examination was done to assess the urticarial severity using the

Urticaria activity score (UAS) (17) which assesses daily pruritus and number of hives,
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and summed over a week, giving the UAS7 score (range: 0–42) with a higher score

meaning higher disease severity. The patients' disease severity levels were graded as
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mild (0-14), moderate (15-29), and severe (30-42).

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All patients were followed up for any adverse or side effects by the primary
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investigator every week till the end of the study.

Laboratory measurements:
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A 4 ml blood sample was withdrawn from all patients and the healthy controls for

biochemical assessment of complete blood count, erythrocyte sedimentation rate,

serum calcium and phosphorus, serum glucose, liver function tests, kidney function

tests. Another 3 ml blood sample was withdrawn at baseline and at the end of the

study then the sera were centrifuged at 3000 rpm, for 10 minutes at 4°c, and then kept
frozen at -80 C for the biochemical evaluation of serum 25(OH) D, high sensitivity C-

reactive protein (hs-CRP), Interleukin 6 (IL6) and Tumor necrosis factor alpha

(TNFα). This analysis was performed by enzyme linked immunosorbent assay

technique (ELISA) (DRG International Inc., Springfield., New Jersey, USA) and

(Quantikine, USA). Levels of 25(OH)D < 20 ng/ml were vitamin D deficient, 21-29

ng/ml were insufficient, and 30ng/ml or more were sufficient or normal.

Ethical consideration

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The study was conducted in accordance with Good Clinical Practice guidelines, and

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the ethical principals in 1964 Helsinki Declaration. This study also applied

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CONSORT guidelines and ICMJE recommendations. The protocol was revised and

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approved by NHTMRI Institution Review Board (IRB no 5432). Prior to participation

all patients and healthy controls were informed about the study protocol and requested
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to sign a written informed consent.
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Statistical analysis
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Statistical analysis was performed using the SPSS statistical program (v.22; SPSS,

Chicago, IL). Data were expressed as the mean and standard deviation (SD) for
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parametric data, and as numbers and percentage for categorical data. To analyze the
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normal distribution of parameters in both groups, the Kolmogorov–Smirnov test was

applied. As a result of the normal distribution of data, the Paired Student t test,
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Unpaired Student t test and Chi-square test were used for data analysis. The

probability of error of 0.05 was considered to be significant, and 0.001 to be highly

significant.
Results

At the baseline of study, there were no significant differences between the CSU

patients and healthy controls regarding the demographic data (age, sex, BMI) and

clinical characteristics (smoking, family history). However, the mean serum 25(OH)

D was significantly lower (p<0.05) and the mean serum IL6, hsCRP, TNFα were

significantly higher (p<0.05) in the patient group as compared to the healthy control.

(Table 1)

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The CSU patients were then divided to study and placebo group, where before the

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alfacalcidol administration there were no significant differences between both groups

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regarding the demographic data, clinical characteristics and all laboratory parameters.

(Table 2)
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Using the UAS7 to assess the disease severity in all CAS patients, we have 37 patients

in the moderate category, total 42 in the severe category and no mild cases.
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After alfacalcidol supplementation, the study group showed highly significant

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increase (p<0.001) in the mean serum 25(OH) D as compared to the placebo group

and their baseline results. In addition, the mean serum IL6, hsCRP, TNFα
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significantly decrease (p<0.01) in the study group in comparison to the placebo group
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and their baseline result at the end of the study. (Table 3, Figure 1, 2, 3)
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Regarding the UAS7, the study group showed improvement where 3 patients became

mild cases, 28 patients became moderate and 7 patients in severe cases as compared

to their baseline data (0,18,20) respectively (Figure 4). The total score of UAS7 is

significantly lower (p<0.01) in the study group after active vitamin D administration

as compared to the placebo group. (Table 3). While the placebo group showed no
significant change in both total score of UAS7 and the number of patients in each

severity level in comparison to their baseline results.

Using the Spearman rank correlation test, there was significant negative correlation

(r= -0.67, p<0.05) between the mean serum 25(OH) D and the total score of UAS7 as

a measure for disease severity.

None of the patients reported discontinuation of the alfacalcdiol, and there were no

adverse events reported.

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Discussion

CSU is one of the most common type of chronic urticaria that is endogenous and is

not triggered by external physical stimuli (2). Vitamin D deficiency is a major

worldwide public health problem affecting all age groups. Vitamin D plays an

important role in the immune system; it activates both innate and adaptive immune

responses (18, 19). It is known that autoimmune reactions have role in CSU

pathogenesis. Since vitamin D deficiency is linked to many autoimmune and allergic

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diseases and there are numerous studies (20-22) have been carried out to investigate

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the association of vitamin D with certain diseases, such as atopic dermatitis and

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psoriasis. Low serum level of 25(OH) D may be associated with CSU. Unfortunately,

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data on CSU and 25(OH) D levels is limited and controversial, hence, we developed

this study to investigate the role of vitamin D deficiency in CSU and the efficacy and
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safety of active vitamin D in CSU management.
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In the present study, we found that the mean serum level of 25(OH) D was lower in

CSU patients as compared to healthy controls (25±1.01 vs 40.2±1.1, respectively).

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This was similar to the results of other studies (11-16, 23, 24) which showed

significantly low level of serum level of 25(OH) D in CSU patients. However, this
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was inaccordance to Lee et al. (25) that found no significant difference (p=0.12) in
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serum 25(OH) D between CSU patients and healthy controls, and Wu et al. (26) that
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reported significant higher serum 25(OH) D in CSU patients.

The discrepancy between studies may be due to the differences in the populations

enrolled, where they differ in time spent outdoors, sun exposure practices, BMI,

physical activity, alcohol intake, and genetic polymorphism.

Our study also found significant negative correlation between serum 25(OH) D and

CSU severity in terms of UAS7 and this was similar to Woo el al. (27) and Rather et
al. (28) where a significant negative correlation was found between vitamin D levels

and UAS7 (P < 0.001). However, this was against Boonpiyathod et al. (29) and Oguz

Topal et al. (15) who found no significant correlation (p=0.23)

Our randomized controlled trial is the first trial to investigate the effect of active

vitamin D on the clinical outcome of CSU. With 0.25ug alfacalcdiol supplementation,

the mean serum 25(OH) D significantly increase in the study group from 22±0.72

ng/ml at the baseline to 42±0.83 ng/ml after 12 weeks. However, there was no

significant change (p<0.05) seen in the placebo group. Also, the UAS7 total score

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significantly decrease (p<0.001) in the study group as compared to the placebo group

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at the end of the study.

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These findings were similar to the results in other studies (18,19) conducted on CSU

patients with cholecalciferol or ergocalciferol supplementations where there were

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significant, rise in the serum 25(OH) D and significant decrease in the UAS7 total
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score in the study group. Unfortunately, only 2 of these studies were randomized

controlled trials.
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Moreover, we reported significant higher mean serum IL6, hsCRP, TNFα level in the
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CSU patients in comparison to the healthy controls and this was similar to other
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studies (30,31) that demonstrated higher level of some proinflammatory cytokines

(IL6, IL10, IL18, TNFα) in the serum of CSU patients, suggesting that these
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cytokines might be used as marker of disease activity.

After 12 weeks, our study group showed significant decrease in the mean serum level

of IL6, hsCRP, TNFα, however this wasn't seen in the placebo group. This supported

the possible anti-inflammatory effects of vitamin D on CSU patients. No other studies

evaluate the level of the cytokines after Vitamin D supplementation

Additional large scale, multicenter, randomized, double blinded for longer duration

are warranted for further evaluation of the potential role of vitamin D in CSU.

Conclusion

This randomized controlled trial concluded that vitamin D deficiency is more

prevalent in CSU patients and this support the role of Vitamin D in CSU

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pathogenesis, in addition it is demonstrated that active vitamin supplementation for

12 weeks as add on therapy to the standard therapy has a beneficial effect on the

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clinical course of the disease as it improve UAS7 total score and the level of the

inflammatory markers with no side effects reported.

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Acknowledgements

The authors wish to acknowledge all the patients who participated in this study, this
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research received no specific grant from any funding agency in the public,
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commercial, or not-for-profit sectors. No financial disclosures were reported by the

authors of this manuscript.

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Figure Legend

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Fig. 1: Mean serum level of IL6 in the study group at baseline and at the end of
the study.

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Fig. 2: Mean serum level of TNFα in the study group at baseline and at the end
of the study.
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Fig. 3: Mean serum level of hsCRP in the study group at baseline and at the end

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of the study.

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Fig. 4: Number of CSU patients in each severity category in UAS7 at the end of
the study
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Table (1): Baseline Demographic data, Clinical characteristics and
Laboratory parameters for both patient and healthy control groups
Baseline evaluation Patient group Healthy control group P value
(n=77) (n=67)
A- Demographic
Data
Age (years) mean ± SD 36.5 ±5.12 (20-56) 39.34±7.23 (22-55) 0.32
(range)
Sex; n (%)
Male 31 (40.2%) 34 (50.7%) 0.71
Female 46 (59.7%) 33 (49.2%)
BMI (kg/m2) mean ± SD 29.47±2.4 30.1±4.6 0.87
B- Clinical
Characteristics -
Duration of disease 6.5± 1.2

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(months) mean ± SD

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Family history; n (%) 23 (23%) 19 (19%) 0.9
C- Laboratory

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Parameters
Serum 25(OD) D levels; 25±1.01 40.2 ± 1.1 0.001**

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mean ± SD
Deficient n (%) 20 (25.9%) 0 (0%) 0.001**
Insufficient n (%)
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Sufficient n (%) 54 (70.1%) 20 (29.8%) 0.01*

Serum IL6 (pg/ml) mean 3 (0.04%) 47 (70.1%) 0.001**

± SD 3.1±0.6 1.3±0.2 0.02*
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Serum TNFα (pg/ml)

mean ± SD 4.3±0.75 1.12±0.3 0.03*
Serum hsCRP (mg/dl)
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mean ± SD 10±1.2 5.3±0.25 0.001**

n: number of patients, SD: standard deviation, BMI: body mass index, IL6: Interlukin 6, TNFα: Tumor
necrosis factor, hsCRP: high sensitive c- reactive protein*(p ≤0.05) is considered significant, **(p
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≤0.001) is considered highly significant.

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Table (2): Baseline Demographics and Clinical characteristics and
laboratory parameters for both Study and Placebo groups
Baseline evaluation Study (n=38) Placebo group (n=39) P
value
A- Demographic
Data
Age (years) mean ± SD 35.2±4. 37 (20-55) 34.6±9.8 (20-56) 0.1
(range)
Sex; n (%) 16 (42.1%) 15 (38.5%)
Male 25 (65.8%) 21 (53.8%) 0.51
Female
BMI (kg/m2) mean ± SD 28.27±3.4 29.2±3.6 0.67
B- Clinical
Characteristics

t
Duration of disease 7.1±0.34 6.5±0.54 0.68

ip
(months) mean ± SD
Family history; n (%) 13(34.3%) 10(25.6%) 0.23

cr
Smoking; n (%) 13 (34.2%) 12 (30.7%) 0.9
Presence of 10 (26.3%) 12 (30.7%) 0.81
angioedema; n(%)
UAS7 score n (%)
Mild
Moderate
0 (0%)
18 (47.3%)
0 (0%)
us
17 (43.6%)
1
0.4
an
Severe 20 (52.6%) 22(56.4%) 0.6

C- Laboratory
M

parameters
Serum 25(OD) D levels;
mean ± SD 22.3 ± 0.72 24.1±0.91 0.1
ed

Deficient n (%) 8 (21.1%) 12 (30.7%) 0.07

Insufficient n (%)
Sufficient n (%) 29 (76.3%) 25 (64.1%) 0.087
pt

Serum IL6 (pg/ml) 1 (2.6%) 2 (5.1%) 0.16

mean ± SD
ce

Serum TNFα (pg/ml) 3.1±0.8 3.2±0.6 0.078

mean ± SD
Serum hsCRP(mg/dl) 4.1±0.21 4.6±0.53 0.091
Ac

mean ± SD
11±0.9 10.1±0.78 0.08
n: number of patients, SD: standard deviation, BMI: body mass index, UAS: urticaria activity score,
IL6: Interlukin 6, TNFα: Tumor necrosis factor, hsCRP: high sensitive c- reactive protein*(p ≤0.05) is
considered significant, **(p ≤0.001) is considered highly significant.
Table (3): End of study Laboratory parameters for both Study and
Placebo groups
Laboratory parameters Study group (n=38) Placebo group (n=39) P value

Serum 25(OD) D levels;

mean ± SD 42 ± 0.83 23±1.1 0.05*
Deficient n (%) 1(2.6%) 12 (30.7%) 0.001**
Insufficient n (%)
Sufficient n (%) 11 (28.9%) 25 (64.1%) 0.01*

Serum IL6 (pg/ml) mean 26 (68.4%) 2 (5.1%) 0.001**

± SD 1.4±0.67 3±0.24 0.05*
Serum TNFα (pg/ml)
mean ± SD 1.24±0.78 4.2±0.31 0.02*

t
Serum hsCRP(mg/dl)

ip
mean ± SD 4.5±0.33 9.3±0.52 0.01*
n: number of patients, SD: standard deviation, IL6: Interlukin 6, TNFα: Tumor necrosis factor, hsCRP:

cr
high sensitive c- reactive protein*(p ≤0.05) is considered significant, **(p ≤0.001) is considered highly
significant.

us
an
M
ed
pt
ce
Ac