10.5826/dpc.1304a272
Introduction: Cytokines are key mediators in immunological and inflammatory conditions, including chronic spontaneous urticaria (CSU).
Objectives: To investigate Th1, Th2, and Th17 cytokine profiles in CSU and to evaluate the possible effect of omalizumab treatment.
Methods: Patients who were followed up for CSU, as well as healthy volunteers, were included in the study. To assess urticaria activity, the 7-day-Urticaria Activity Score (UAS-7), the Urticaria Control Test (UCT), and the Chronic Urticaria Quality of Life Questionnaire (CU-QoL) were filled. Serum levels of IL-6, IL-17, IL-31, eotaxin, RANTES, TNF-α, and TSLP were analyzed by ELISA and compared in CSU and control groups. The patients were analyzed in two groups as the omalizumab group and the non-omalizumab group based on their treatment status.  
Results: Total IgE, ESR, CRP, RANTES, and TNF-a were significantly different in the overall comparison of the three groups: CSU-receiving omalizumab, CSU-not receiving omalizumab, and control groups (P &lt;0.01, 0.015, &lt;0.01, &lt;0.01 and &lt;0.01 respectively). Total IgE, CRP, RANTES, and TNF-α values were similar in those who received and did not receive omalizumab, yet these biomarkers were significantly higher in both groups than in the control group (P &lt; 0.05). Statistical significance in ESR was observed only between the CSU-receiving omalizumab group and the control group (P = 0.01). Within the CSU patients, there was a slight but significant correlation between UCT and TNF-α (P = 0.008, r = 0.32) and IL-17 (P = 0.06, r = 0.33) levels.
Conclusions: The investigated cytokine profile in CSU patients may differ from healthy controls, particularly with the higher levels of RANTES and TNF-α, and omalizumab treatment does not seem to affect that profile in CSU patients.
text/xml
2160-9381
3325
en
Ali Fuat Kalyoncu
https://creativecommons.org/licenses/by-nc/4.0
Dermatology Practical & Conceptual
IL-17
Cytokine Profiles of Chronic Urticaria Patients and the Effects of Omalizumab Treatment
Text.Serial.Journal
https://dpcj.org/index.php/dpc
Original Article
2023-10-31
2023-03-13
2023-10-31
2024-01-16
e2023272
Dermatol Pract Concept
Introduction: Cytokines are key mediators in immunological and inflammatory conditions, including chronic spontaneous urticaria (CSU).
Objectives: To investigate Th1, Th2, and Th17 cytokine profiles in CSU and to evaluate the possible effect of omalizumab treatment.
Methods: Patients who were followed up for CSU, as well as healthy volunteers, were included in the study. To assess urticaria activity, the 7-day-Urticaria Activity Score (UAS-7), the Urticaria Control Test (UCT), and the Chronic Urticaria Quality of Life Questionnaire (CU-QoL) were filled. Serum levels of IL-6, IL-17, IL-31, eotaxin, RANTES, TNF-α, and TSLP were analyzed by ELISA and compared in CSU and control groups. The patients were analyzed in two groups as the omalizumab group and the non-omalizumab group based on their treatment status.  
Results: Total IgE, ESR, CRP, RANTES, and TNF-a were significantly different in the overall comparison of the three groups: CSU-receiving omalizumab, CSU-not receiving omalizumab, and control groups (P &lt;0.01, 0.015, &lt;0.01, &lt;0.01 and &lt;0.01 respectively). Total IgE, CRP, RANTES, and TNF-α values were similar in those who received and did not receive omalizumab, yet these biomarkers were significantly higher in both groups than in the control group (P &lt; 0.05). Statistical significance in ESR was observed only between the CSU-receiving omalizumab group and the control group (P = 0.01). Within the CSU patients, there was a slight but significant correlation between UCT and TNF-α (P = 0.008, r = 0.32) and IL-17 (P = 0.06, r = 0.33) levels.
Conclusions: The investigated cytokine profile in CSU patients may differ from healthy controls, particularly with the higher levels of RANTES and TNF-α, and omalizumab treatment does not seem to affect that profile in CSU patients.
Ali Fuat Kalyoncu
2023/10/31
10.5826/dpc.1304a272
e2023272
Hacettepe University Faculty of Medicine, Department of Chest Diseases, Division of Allergy and Immunology, Ankara, Turkey 
2160-9381
IL-17
en
e2023272
Giménez-Arnau AM, DeMontojoye L, Asero R, et al. The Pathogenesis of Chronic Spontaneous Urticaria: The Role of Infiltrating Cells. J Allergy Clin Immunol Pract. 2021;9(6):2195-2208. DOI: 10.1016/j.jaip.2021.03.033. PMID: 33823316.
Cytokine Profiles of Chronic Urticaria Patients and the Effects of Omalizumab Treatment
https://dpcj.org/index.php/dpc/article/download/3325/2381
        Cytokine Profiles of Chronic Urticaria Patients
          and The Effect of Omalizumab Treatment
Ozge Can Bostan1, Ebru Damadoglu1, Basak Ezgi Sarac2, Busra Kilic2, Umit Murat Sahiner3,
                Cagatay Karaaslan2, Gul Karakaya1, Ali Fuat Kalyoncu1


1 Hacettepe University Faculty of Medicine, Department of Chest Diseases, Division of Allergy and Immunology, Ankara, Turkey
2 Hacettepe University Faculty of Science, Department of Biology, Molecular Biology Section, Ankara, Turkey
3 Hacettepe University Faculty of Medicine, Department of Pediatric Allergy and Asthma, Ankara, Turkey



Key words: Chronic spontaneous urticaria, biomarker, cytokine, TNF-α, IL-17
Citation: Can Bostan O, Damadoglu E, Sarac BE, et al. Cytokine Profiles of Chronic Urticaria Patients and The Effect of Omalizumab
Treatment. Dermatol Pract Concept. 2023;13(4):e2023272. DOI: https://doi.org/10.5826/dpc.1304a272
Accepted: June 26, 2023; Published: October 2023
Copyright: ©2023 Can Bostan et al. This is an open-access article distributed under the terms of the Creative Commons Attribution-
NonCommercial License (BY-NC-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use,
distribution, and reproduction in any medium, provided the original authors and source are credited.
Funding: The study was supported by Hacettepe University Scientific Research Projects Coordination Unit (Project No: THD-2020-18771).
Competing Interests: None.
Authorship: All authors have contributed significantly to this publication.
Corresponding Author: Ozge Can Bostan, Hacettepe Üniversitesi Hastanesi, 06230, Altındağ, Ankara, Turkey. Tel: +905079901336
E-mail: ozge.can20@hotmail.com




  ABSTRACT             Introduction: Cytokines are key mediators in immunological and inflammatory conditions, including
                       chronic spontaneous urticaria (CSU).
                       Objectives: To investigate Th1, Th2, and Th17 cytokine profiles in CSU and to evaluate the possible
                       effect of omalizumab treatment.
                       Methods: Patients who were followed up for CSU, as well as healthy volunteers, were included in the
                       study. To assess urticaria activity, the 7-day-Urticaria Activity Score (UAS-7), the Urticaria Control Test
                       (UCT), and the Chronic Urticaria Quality of Life Questionnaire (CU-QoL) were filled. Serum levels
                       of IL-6, IL-17, IL-31, eotaxin, RANTES, TNF-α, and TSLP were analyzed by ELISA and compared in
                       CSU and control groups. The patients were analyzed in two groups as the omalizumab group and the
                       non-omalizumab group based on their treatment status.
                       Results: Total IgE, ESR, CRP, RANTES, and TNF-a were significantly different in the overall com-
                       parison of the three groups: CSU-receiving omalizumab, CSU-not receiving omalizumab, and control
                       groups (P <0.01, 0.015, <0.01, <0.01 and <0.01 respectively). Total IgE, CRP, RANTES, and TNF-α
                       values were similar in those who received and did not receive omalizumab, yet these biomarkers were
                       significantly higher in both groups than in the control group (P < 0.05). Statistical significance in ESR
                       was observed only between the CSU-receiving omalizumab group and the control group (P = 0.01).
                       Within the CSU patients, there was a slight but significant correlation between UCT and TNF-α
                       (P = 0.008, r = 0.32) and IL-17 (P = 0.06, r = 0.33) levels.




Original Article | Dermatol Pract Concept. 2023;13(4):e2023272                                                                       1
                      Conclusions: The investigated cytokine profile in CSU patients may differ from healthy controls, par-
                      ticularly with the higher levels of RANTES and TNF-α, and omalizumab treatment does not seem to
                      affect that profile in CSU patients.




Introduction                                                       atopic dermatitis and acute urticaria, implying that it proba-
                                                                   bly serves to recruit and activate eosinophils and represents
Chronic spontaneous urticaria (CSU) is a common clinical           a biomarker of lesional activity [14].
condition characterized by itchy wheals and/or swelling that          Many markers have been explored for conceivable re-
resolves within 24 hours and lasts for at least six weeks [1].     lations with CSU activity, but the number of studies that
Symptoms are associated with impaired quality of life, and         predict response to treatment and assess the levels of Th1,
as a result, there is a high probability of experiencing depres-   Th2, and Th17 cytokines together is limited, and the re-
sion, anxiety, and sleep disorders. Treatment response and         sults showed a variation in cytokine profiles between CSU
monitoring of disease activity in CSU are mostly based on          patients and healthy control groups, with no common and
the use of patient-reported outcomes. [2]. However, the main       definite increase or decrease for these markers [15-19]. The
limitation of these extensive questionnaires for the assess-       objective of this study was to evaluate the Th1, Th2, and
ment of CSU is their subjective nature.                            Th17 serum cytokine levels in CSU and to document the pos-
    Recently, studies have highlighted that certain cytokines      sible effect of omalizumab on these biomarkers.
can be considered as potential biomarkers related to the
disease [3]. Moreover, the emergence of such biomarkers            Methods
contributes to studies on new biological agents in the man-
agement of resistant CSU and supports personalized treat-          Study Subjects
ment and follow-up [4, 5].                                         The present case-control study included CSU-diagnosed pa-
    Activation and degranulation of mast cells and ­migration      tients, aged ≥18 years, and followed up at the Adult Allergy
of basophils to the tissue are frequently observed in the in-      and Immunology Clinic between December 2019 - Decem-
flammation of urticaria. In addition, uncontrolled T-cell          ber 2021. The diagnosis of CSU was made based on the re-
activation has been reported in skin biopsies from the
­                                                                  currence of spontaneous wheals lasting 24 hours for at least
­lesional/non-lesional areas and peripheral circulation of CSU     6 weeks, according to the guidelines [1]. Patients who had
patients [6]. In this regard, a high percentage of inflamma-       inducible or known caused- urticaria, accompanied colla-
tory cells are composed of T lymphocytes and monocytes,            gen tissue disease or urticarial vasculitis, patients receiving
suggesting that T cells play an important role in the patho-       corticosteroid therapy for any reason, and pregnant women
genesis of CSU [7].                                                were excluded from the study. Hemogram, C-reactive pro-
    As a Th1 mediator, tumor necrosis factor-α (TNF-α) is          tein (CRP), erythrocyte sedimentation rate (ESR), D-dimer,
a candidate biomarker for urticaria released by other in-          thyroid stimulating hormone (TSH), anti-TPO, liver, and
                                                                   ­
flammatory cells that can be detected in the area of urticaria     kidney function tests were performed on each patient.
lesions together with skin mast cells [8]. The fact that in-          Omalizumab was administered subcutaneously at 300
flammatory mediators such as IL-6 and IL-31, which are in-         mg once a month for the indication of chronic urticaria in
volved in Th2 inflammation, have higher levels in urticaria        patients whose symptoms have not been controlled with
patients and regress with treatment or remission, promises         antihistamines as stated in the guidelines [1]. Patients were
that these and similar biomarkers may be important in the          analyzed according to their omalizumab treatment status by
etiopathogenesis and treatment modalities of CSU [4, 9-12].        dividing them into two groups, as those who received omali-
    Many chemokines and enzymes involved in the patho-             zumab and those who did not. In order to evaluate the effec-
genesis of urticaria are also being investigated. Among the        tiveness of the treatment for the omalizumab group, patients
chemokines, RANTES is a protein that especially attracts T         who had been receiving omalizumab therapy for at least 4
cells to the site of inflammation and has been proposed to         months were included.
be of potential importance in the etiopathogenesis of CSU             Age- and gender-matched healthy volunteer participants
without correlation with disease activity and treatment re-        were recruited as the control group after being informed about
sponse [13]. Eotaxin is a chemokine that specifically regulates    the procedures and purpose of the study. Venous blood samples
eosinophil selection and recruitment. Circulating eotaxin          (10 mL) from patients and controls were centrifuged at 1500 g
levels have been shown to increase during exacerbations of         for 10 minutes, and samples were aliquoted and stored at -80°C.



2                                                                      Original Article | Dermatol Pract Concept. 2023;13(4):e2023272
Assessment of Urticaria Activity                                     with Dunn test was used to compare the biomarkers of CSU
To evaluate urticaria activity, the 7-day-Urticaria Activity         patients who received omalizumab and those who did not
Score (UAS-7), Urticaria Control Test (UCT) scores, and              receive omalizumab with those of the control group. Values
Chronic Urticaria Quality of Life Questionnaire (CU-QoL)             of P < 0.05 were interpreted as statistically significant.
were filled out [20-23].                                                The study was approved by the Ethics Committee of
                                                                     Hacettepe University Hospital (Approval No: GO-19/1032)
Protein Assessment by Enzyme-Linked                                  and all participants gave written consent before the study
Immunosorbent Assay (ELISA)                                          procedures.

Serum levels of IL-6, IL-8, IL-17, IL-25, IL-31, IL-33,
­Eotaxin, RANTES, GM-CSF, TNF-α, TSLP were analyzed
                                                                     Results
in triplicate by ELISA using a commercial kit (IL-6: Abcam;
­IL-8, IL-17, IL-25, IL-31, IL-33, Eotaxin, RANTES, GM-              The study included 78 patients with a diagnosis of CSU fol-
CSF, TSLP: R&D Systems; TNF-α: Mabtech) using the En-                lowed in the Hacettepe University Adult Allergy and Immu-
Sight Multimode Plate Reader (PerkinElmer) according to              nology Clinic and 18 healthy participants.
the manufacturer guidelines.                                            The mean age of CSU patients was 40.2 ± 12.5 years
                                                                     and 57 (73.1%) of them were female (Table 1). The median
Statistical Analysis                                                 CSU duration of the patients was 48 (IQR: 15-120) months.
IBM SPSS Statistics, version 25.0 software (IBM Corp.),              Comorbidities were determined as, 12 (15.4%) asthma, 11
was utilized for the statistical analyses. The normal dis-           (14.1%) allergic rhinitis, 8 (10.3%) hypertension, 5 (6.4%)
tribution of continuous variables was checked via the                diabetes mellitus, 10 (12.8%) hypothyroidism, 5 (6.4%)
­Kolmogorov-Smirnov test and analyzed as mean ± standard             rheumatological, 4 (5.1%) cardiac, 3 (2.6%) renal, and 1
deviation (SD) in a normal distribution, otherwise as me-            (1.3%) psychiatric disorder. There was no difference in co-
dian [­
      lower-upper quartile] values. Patient demographics             morbidities between the two groups receiving and not receiv-
were analyzed using the Chi-square test to compare distri-           ing omalizumab. Of the patients, 42 (53.8%) were receiving
butions of gender and comorbidities, and the Mann-Whit-              omalizumab, with a median duration of 18 months (9-30)
ney U test to compare the UCT, UAS-7, CU-QoL scores, and             and a CSU duration of 66 (31.2-138) months.
CSU duration in both groups. Spearman's rank correlation                The median UCT score of the patients was 10 (5-13),
test was applied for correlation analysis. The Kruskal-Wallis        and the median UAS-7 score was 15 (4-27). UCT scores were


  Table 1. Comparisons of the patient characteristics according to the status of omalizumab therapy.
                                                                 Omalizumab group          Non-omalizumab group
               Variables                  Total (N = 78)              (N = 42)                   (N = 36)                  P value
 Age, mean ± SD, years                      40.2 ± 12.5             42.4 ± 13.7                    38.5 ± 11.9              0.19
 Female gender, N (%)                        57 (73.1)               33 (78.6)                      24 (66.7)               0.30
 CSU duration, median (IQR),                48 (15-120)            66 (31.2-138)                    24 (2-96)               0.001
 months
 Comorbidities, N (%)
   Asthma                                    12 (15.4)                9 (21.4)                        3 (8.6)               0.20
   Rhinitis                                  11 (14.1)                5 (11.9)                       6 (17.1)               0.53
   Hypertension                              8 (10.3)                 6 (14.3)                        2 (5.6)               0.18
   Diabetes mellitus                          5 (6.4)                  4 (9.5)                        1 (2.8)               0.36
   Hypothyroidism                            10 (12.8)                6 (14.3)                       4 (11.1)               0.74
   Rheumatologic disorders                    5 (6.4)                  3 (7.1)                        2 (5.6)               0.57
   Cardiac disorders                          4 (5.1)                  2 (4.8)                        2 (5.6)               0.63
   Renal disorders                            2 (2.6)                  1 (2.4)                        1 (2.8)               0.71
   Psychiatric disorders                      1 (1.3)                  1 (2.4)                         0 (0)                 n/a
 UCT score, median (IQR)                     10 (5-13)               12 (8-14)                       8 (2-11)              <0.001
 UAS-7 score, median (IQR)                   15 (4-27)               8.5 (1-27)                    22 (13-27)               0.04
 CU-QoL score %, median (IQR)                  27.1               22.8 (14.4-45.3)              33.6 (17.3-56.5)            0.14
                                            (15.2-45.7)

CSU = Chronic Spontaneous Urticaria; CU-QoL = Chronic Urticaria Quality of Life; IQR = Interquartile range; n/a = non applicable;
SD = standard deviation; UAS-7 = 7-day Urticaria Activity Score; UCT = Urticaria Control Test.



Original Article | Dermatol Pract Concept. 2023;13(4):e2023272                                                                      3
higher in the group receiving omalizumab (median [IQR]: 12          (P values, respectively, 0.001, 0.06, 0.02 and <0.001). Among
[8-14] versus 8 (2-11), P < 0.001). UAS-7 scores were lower         the biomarkers, RANTES and TNF-α levels were more ele-
in the omalizumab group (8.5 (1-27) versus 22 [13-27],              vated in CSU patients (both P values <0,001). The eosinophil
P = 0.04). There was no significant difference between the          counts and percentages, eotaxin, IL-6, TSLP, IL-17, and IL-
quality-of-life scores in both groups (Table 1).                    31 levels were similar between the CSU and control groups
    In the comparison of the CSU and control groups; CRP,           (Figure 1). There was no significant difference in eosino-
ESR, D-dimer, and Total IgE levels were higher in CSU               phil count/percentage, Total IgE, erythrocyte sedimentation
patients (n=78) compared to the control group (N = 18)              rate, CRP, eotaxin, IL-6, TSLP, RANTES, TNF-α, IL-17, and




                      Figure 1. Comparison of biomarker levels in chronic spontaneous urticaria and control groups
                      CSU = chronic spontaneous urticaria; OMA = omalizumab; ns = non-significant.



4                                                                       Original Article | Dermatol Pract Concept. 2023;13(4):e2023272
 IL-31 levels between the groups that were receiving and not            was observed only between the CSU-receiving omalizumab
 receiving omalizumab (Figure 1 and Table 2).                           group and the control group (CSU/OMA versus control, P =
     In the overall comparison of the three groups:                     0.01). D-dimer levels between patients and healthy controls
 CSU-receiving omalizumab, CSU-not receiving omalizumab,                were higher in the total CSU group (P = 0.02); however, this
 and control groups, Total IgE, ESR, CRP, RANTES, and                   did not constitute as evidence for a correlated association
 TNF-α were significantly different (P <0.01, 0.015, <0.01,             and lost significance in the overall comparison of the three
 <0.01 and <0.01 respectively). Total IgE, CRP, RANTES, and             groups (P = 0.05).
 TNF-α values were similar between those who received and                   Within the CSU patients, there was a slight but signifi-
 did not receive omalizumab, but both groups were signifi-              cant correlation between UCT scores and TNF-α (P = 0.008,
 cantly different from the control group in terms of these bio-         r = 0.32) and IL-17 (P = 0.06, r = 0.33) levels (Figure 2).
 markers. Total IgE, CRP, RANTES, and TNF-a were higher in              Serum levels of IL-8, IL-25, IL-33, and GM-CSF were also
 patients receiving and not receiving omalizumab compared               analyzed by ELISA; however, their levels were below the de-
 to the control group (Table 2). Statistical significance in ESR        tection ranges of the kits.



               Table 2. Comparisons of biomarker profile by omalizumab status and control.
                                                                                                             Pa                     Pb
                               CSU / OMA            CSU / Non-OMA              Control        OMA vs    Non-OMA       OMA vs
       Variables*               (n = 42)               (n = 36)                (n = 18)       Control   vs Control   Non-OMA
 Age, years                    42.4 ± 13.7            38.5 ± 11.9              38 (30-47)        ns         ns           ns        0.37
 Female gender, n (%)           33 (78.6)               24 (66.7)              38 (30-47)        ns         ns           ns        0.43
 Eosinophils, cells/μL       100 (100-215)           100 (100-200)          115 (100-200)        ns         ns           ns        0.88
 Eosinophils, %             1.60 (0.82-2.62)        1.55 (1.02-2.67)          1.5 (1.2-2.6)      ns         ns           ns        0.96
 D-dimer, µg/mL             0.35 (0.24-0.51)        0.41 (0.23-0.69)       0.24 (0.19-0.38)      ns         ns           ns        0.05
 Total IgE, IU/mL            232 (87.1-358)          105 (37.4-248)        23.6 (11.9-50.6)    <0.01       <0.01         ns       <0.01
 ESR, mm/h                     10.5 (6-20)             10 (4-15)                 3 (2-6)        0.01        ns           ns       0.015
 CRP, mg/L                   0.43 (0,29-0.7)        0.54 (0.27-1.03)       0.20 (0.11-0.37)     0.01       <0.01         ns       <0.01
 Eotaxin, pg/mL             36.2 (25.1-54.5)        35.7 (19.4-50.5)        24.8 (17-46.5)       ns         ns           ns        0.37
 IL-6, pg/mL                1.44 (0.82-2.76)        1.37 (0.90-3.93)          1.0 (0.7-1.6)      ns         ns           ns        0.41
 TSLP, pg/mL                27.8 (0.72-582.9)      12.2 (0.32- 149.3)      93.6 (6.5-793.0)      ns         ns           ns        0.41
 RANTES, pg/mL             3548 (3108-4003)        3483 (2950-3894)        664.4 (640-743)     <0.01       <0.01         ns       <0.01
 TNF-α, pg/mL               35.1 (0.29-605.3)      156.7 (33.08-392)         1.8 (1.5-2.91)    0.016       <0.01         ns       <0.01
 IL-17, pg/mL               58.6 (1.75-263.8)       47.7 (8.2-268.8)        100 (15.8-639)       ns         ns           ns        0.31
 IL-31, pg/mL              632.2 (100.8-2498)      743.2 (121.3-3447)      213.1 (9-633.6)       ns         ns           ns        0.21

*Categorical variables were presented with frequencies and percentages (%) and continuous variables as mean ± standard deviation or median
(IQR).
CSU; Chronic spontaneous urticaria, OMA: Omalizumab
Pa; Pairwise comparisons between the groups
Pb; Kruskal-Wallis test for nonparametric variables for the comparison of the three groups
C; Chi-Square Test
ns: non-significant




 Figure 2. Correlation graphs between urticaria control test and IL-17 /TNF-α levels.



 Original Article | Dermatol Pract Concept. 2023;13(4):e2023272                                                                       5
Conclusions                                                       Therefore, pharmacological inhibition of the interaction
                                                                  between TSLP and its receptor or antibody-mediated TSLP
In the current study, the biomarker profile in CSU was in-        neutralization was discussed to be a possible option in the
vestigated by comparing the Th1, Th2, and Th17 cytokines,         treatment of CSU patients [35]. However, the number of
which are considered to be valuable in the pathogenesis, in       studies examining serum TSLP levels in CSU is limited. Metz
CSU patients and healthy controls. Of the biomarkers studied      et al. reported no significant increase in TSLP levels in CSU
(TNF-α, IL-6, IL-31, TSLP, IL-17, eotaxin, RANTES), TNF-α         patients [32]. In our study, TSLP levels showed variation in
and RANTES were considered as potential biomarkers of             healthy and CSU samples, and no significant difference was
CSU, while it was observed that the effect of omalizumab          detected between the groups. This suggests that since TSLP
treatment was not through these biomarkers. Consistent            is a more target-oriented molecule, its levels in CSU patients
with the literature, in our study, TNF-α levels were signifi-     may be more significant in assessing lesioned skin rather
cantly higher in the CSU patient group [24]. This can be ex-      than as a serum biomarker.
plained by the theory previously presented by Walsh et al.           It has been shown that IL-31, mainly secreted by Th2
that dermal mast cells include a high amount of immunore-         cells, causes pruritus by activating the IL-31 receptor on
active TNF-α in their granules and that they can be rapidly       sensorial neurons, hence, it is thought to be an important
released into the extracellular area by degranulation [25].       interleukin in skin-related inflammation such as atopic
In the comparison of patients receiving and not receiving         dermatitis [36-38]. Additionally, studies have shown that
omalizumab treatment, although TNF-α levels were lower in         anti-IL-31 treatment significantly reduces/prevents itching
those receiving omalizumab treatment, no statistically signif-    [36,39-42]. Moreover, in addition to the lesioned skin sam-
icant change was observed. Similarly, in the study by Noga        ples of CSU patients, high levels of IL-31 were also detected
et al, in which 19 participants were compared, no significant     in serum samples [38,43]. Besides, in a study conducted with
difference was observed in TNF-α levels between the omal-         15 CSU patients who were highly responsive to omalizumab
izumab and placebo groups [26]. However, in a case series         treatment, a decrease in IL-31 levels was observed after
                                                                  ­
of patients who did not respond to omalizumab, TNF-α an-          ­treatment [40]. In our current study, there was a tendency for
tagonists were noticed to be efficacious in 60% of 20 CSU         higher IL-31 levels in CSU patients. If the sample size in the
patients [27]. This suggests that TNF-α may be a potential        control group was larger, it is believed that the IL-31 levels
biomarker for determining disease activity, but it is insuffi-    between the CSU and control groups would have reached a
cient to assess omalizumab treatment response, but may be         significant difference.
an alternative pathway in patients resistant to omalizumab.          Studies investigating the function of cytokines in CSU indi-
    It has been reported that IL-6 which is known to play         cated that plasma levels of IL-17 were significantly increased
a crucial role in inflammatory responses, is also detected in     in relation to disease severity compared to the control group
high concentrations in CSU patients, and it has been stated       [6,38,44]. Besides, there are studies showing that plasma IL-
that IL-6 signaling may be considered in the pathogenesis         17 levels in CSU patients are similar, and even lower than,
and inflammatory activation of this disease [28]. High IL-6       healthy controls [45]. Previous studies demonstrated that
level has been related to disease severity and activity in many   the levels of IL-17 were higher in autologous serum skin
studies, and it has been proposed that IL-6 may be a good         ­testing-positive CSU patients [8]. In our study, there was no
biomarker for CSU disease [15,29, 0]. On the other hand,          difference in IL-17 levels between CSU and control groups,
there are also studies showing that IL-6 is not related to dis-   but a significant correlation was observed between IL-17 level
ease activity in CSU [31,32]. In a study by Noga et al, inves-    and urticaria control test among CSU patients, which sup-
tigating the omalizumab effect on inflammatory mediators          ports previous studies [8]. This may be due to the fact that
in moderate and severe allergic asthma, no statistically sig-     autologous serum skin testing was not performed in our study
nificant change was observed in IL-6 levels after omalizumab      and IL-17 levels were not measured by classifying accordingly.
treatment [33]. In the present study, IL-6 levels were also          Eotaxin is a potent agonist for the Cysteine-Cysteine
comparable between the study groups. Additionally, similar        (CC) chemokine receptor-3, which attracts eosinophils to
results were observed in those receiving and not receiving        the skin, thus suggesting its involvement in the pathophys-
omalizumab. Therefore, IL-6, which has many important             iology of CSU. In a study by Tedeschi et al, it was indicated
physiological and anti-inflammatory functions such as in-         that serum eotaxin levels in 100 CSU patients were slightly
flammation, fever, and tumorigenesis, has not been consid-        higher in chronic urticaria patients and were correlated with
ered as a specific and reliable marker for CSU.                   the disease severity. In our analysis, eotaxin levels were com-
    TSLP is a cytokine with a critical role in regulating in-     parable in healthy controls and CSU patients.
flammatory responses. TSLP was observed higher in the le-            RANTES promotes the mast cell progenitors for differentia-
sions than in non-lesional skin areas of CSU patients [34].       tion and activation, thereby inducing the histamine release, and



6                                                                     Original Article | Dermatol Pract Concept. 2023;13(4):e2023272
is therefore considered to be involved in CSU p
                                              ­ athogenesis [46].          7. Elias J, Boss E, Kaplan AP. Studies of the cellular infiltrate of chronic
In a study by Puxeddu et al, levels of RANTES and IL-8 were                   idiopathic urticaria: prominence of T-lymphocytes, monocytes,
                                                                              and mast cells. J Allergy Clin Immunol. 1986;78(5 Pt 1):914-918.
quantified in CSU patients, and RANTES was observed to
                                                                              DOI: 10.1016/0091-6749(86)90240-x. PMID: 3491100.
be remarkably higher in CSU compared to healthy controls.
                                                                           8. Atwa MA, Emara AS, Youssef N, Bayoumy NM. Serum concen-
However, no association was found between other markers                       tration of IL-17, IL-23 and TNF-α among patients with chronic
and RANTES [13]. Consistent with these findings, in the cur-                  spontaneous urticaria: association with disease activity and autol-
rent study, RANTES levels were detected to be higher in CSU                   ogous serum skin test. J Eur Acad Dermatol Venereol. 2014;28(4):|
patients regardless of disease activity.                                      469-474. DOI: 10.1111/jdv.12124. PMID: 23451767.
                                                                           9. Takahagi S, Mihara S, Iwamoto K, et al. Coagulation/fibrinolysis
    This study had certain limitations. First, due to the
                                                                              and inflammation markers are associated with disease activity
cross-sectional study design, the study outcomes were not
                                                                              in patients with chronic urticaria. Allergy. 2010;65(5):649-656.
fully sufficient to evaluate the efficacy of omalizumab treat-                DOI: 10.1111/j.1398-9995.2009.02222.x. PMID: 19845571.
ment on biomarkers. It would be more reliable to analyze                  10. Altrichter S, Hawro T, Hänel K, et al. Successful omalizumab
the present outcomes with longitudinal studies. However,                      treatment in chronic spontaneous urticaria is associated with
despite its cross-sectional design, the fact that patients have               lowering of serum IL-31 levels. J Eur Acad Dermatol Vene-
                                                                              reol. 2016;30(3):454-455. DOI: 10.1111/jdv.12831. PMID:
been on omalizumab treatment for a long time and the cyto-
                                                                              25371135.11. Romano C, Sellitto A, De Fanis U, et al. Omal-
kine profiles of those receiving and not receiving ­omalizumab
                                                                              izumab for difficult-to-treat dermatological conditions: clinical
were similar despite better clinical scores, suggests that                    and immunological features from a retrospective real-life expe-
omalizumab might be effective through different pathways                      rience. Clin Drug Investig. 2015;35(3):159-168. DOI: 10.1007
than these cytokines. The second limitation was the limited                   /s40261-015-0267-9. PMID: 25578818.
number of participants in the control group. Some p-values                11. Yalcin AD, Celik B, Gumuslu S. D-dimer levels decreased in se-
                                                                                vere allergic asthma and chronic urticaria patients with the omal-
could be more significant with a larger sample size in the
                                                                                izumab treatment. Expert Opin Biol Ther. 2014;14(3):283-286.
control group.
                                                                                DOI: 10.1517/14712598.2014.875525. PMID: 24359555.
    In conclusion, our results suggest that the investigated              12.   Puxeddu I, Panza F, Pratesi F, et al. CCL5/RANTES, sVCAM-1,
cytokine profile in CSU patients may differ from healthy                        and sICAM-1 in chronic spontaneous urticaria. Int Arch Allergy
controls and omalizumab does not seem to affect that profile                    Immunol. 2013;162(4):330-334. DOI: 10.1159/000354922.
in CSU patients.                                                                PMID: 24157824.
                                                                          13.   Hossny E, Aboul-Magd M, Bakr S. Increased plasma eo-
                                                                                taxin in atopic dermatitis and acute urticaria in infants and
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