Safety and efficacy of h1-antihistamines plus ranitidine in refractory Chronic Spontaneous Urticaria

Safety and efficacy of h1-antihistamines plus ranitidine in refractory Chronic Spontaneous Urticaria | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Safety and efficacy of h1-antihistamines plus ranitidine in refractory Chronic Spontaneous Urticaria Yu Zhou, Bei Wang, Xinyu Li, Kai Chen, Ruili Jiang, Zilu Qu, Liuqing Chen, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7241257/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Some patients with chronic spontaneous urticaria (CSU) remain inadequately controlled despite receiving double doses of H1-antihistamines (H1-AH). The high cost of omalizumab, coupled with the risk of allergic reactions in some patients, highlights the need for alternative treatment options for these refractory cases. Objective This study aimed to assess the efficacy and safety of adding H1-AH plus ranitidine to the original treatment in a subset of patients with refractory urticaria. Methods This was a randomized, open-label study involving patients with CSU that remained uncontrolled after ≥ 2 weeks of double-dose H1-AH therapy. The primary endpoints were the Weekly Urticaria Activity Score (UAS7) response (score < 7) and the Urticaria Control Test (UCT) response (score ≥ 12) at week 12. Results A total of 33 patients with refractory CSU were enrolled in this study. At week 12, 16 patients (48%) achieved a UAS7 response (score < 7), while 15 patients (45%) attained disease control (UCT ≥ 12). Overall, 21 patients (64%) showed an improvement of ≥ 5 points in the Weekly Itch Severity Score (ISS7). There were also significantly greater improvements in the Dermatology Life Quality Index (DLQI) (-2). Regarding adverse reactions, the treatment was well tolerated. A total of 4 (12%) patients experiencing AEs after the addition of ranitidine. Conclusions In refractory CSU patients with the following characteristics: short disease duration, baseline UAS7 score < 25, wheal-type skin lesions without excoriations, negative autologous serum skin test (ASST), or concomitant cholinergic urticaria, ranitidine add-on therapy may improve treatment response rates. Antihistamines Chronic spontaneous urticaria Efficacy Refractory Ranitidine Figures Figure 1 Figure 2 Figure 3 Figure 4 Introduction Urticaria is a common, heterogeneous inflammatory skin disorder characterized by recurrent pruritic wheals, angioedema, or both [ 1 ]. With a lifetime prevalence reaching 20%[ 2 ], chronic urticaria (CU)—defined as symptoms persisting for > 6 weeks—manifests as spontaneous wheals with or without angioedema, irrespective of inducible triggers[ 3 ]. Globally, CU affects 0.5–1% of the population, typically lasting 1–5 years. [ 3 , 4 ] This condition imposes substantial patient and societal burdens, severely compromising quality of life (QoL)[ 4 ]. Treatment responses exhibit marked interindividual variability, reflecting the disease's clinical heterogeneity[ 5 ]. Current guidelines recommend second-generation H1-antihistamines (sgAHs) at standard doses as first-line therapy for chronic spontaneous urticaria (CSU)[ 6 ]. While approximately 50% of CU patients respond to sgAHs[ 7 ], those with inadequate symptom control after 2–4 weeks (or earlier if symptoms are severe) may receive up to 4-fold dose escalation[ 2 , 8 , 9 ]. For patients unresponsive to maximized antihistamine therapy, omalizumab is recommended as second-line add-on treatment[ 8 ]. Cyclosporine is reserved as third-line therapy exclusively for severe, refractory cases failing combined antihistamine and omalizumab treatment[ 10 ], though its use is limited by significant safety concerns [ 8 ]. Omalizumab, a recombinant humanized monoclonal anti-IgE antibody, is an approved treatment for CSU[ 11 ]. Randomized controlled trial evidence demonstrates that nearly 50% of patients still experience persistent wheals and pruritus despite 4-fold increased antihistamine doses, requiring biologic intervention with omalizumab[ 7 ]. The optimal dosing regimen is well-established in current guidelines[ 2 , 12 ]. While licensed omalizumab doses show efficacy in H1-antihistamine-refractory CSU, approximately 30% of patients remain symptomatic after ≥ 6 months of therapy[ 2 , 12 ]. Despite proven efficacy, omalizumab's widespread adoption faces multiple socioeconomic and systemic barriers. Its substantially higher cost relative to conventional antihistamines, combined with variable reimbursement policies and restrictive eligibility criteria, creates significant access challenges for refractory urticaria patients[ 13 ]. Global availability shows marked geographical disparities, with particularly limited access in resource-limited settings. Furthermore, treatment-emergent hypersensitivity reactions and other adverse events may further constrain its clinical utility.The suboptimal response observed in some patients remains multifactorial, necessitating further research to optimize therapeutic strategies for this population. Meanwhile, clinical studies have investigated alternative approaches, including H1-antihistamine combination therapies[ 14 , 15 ]. In clinical practice, sgAHs combined with ranitidine are commonly used to treat urticaria. Previous studies have shown improved response rates with ranitidine combination therapy in acute urticaria[ 16 ]. Notably, Ogawa et al.'s retrospective study demonstrated higher remission rates in H1-antihistamine-resistant chronic urticaria patients receiving adjunctive H2-antihistamine (ranitidine) therapy[ 17 ]. However, robust clinical data on this combination's efficacy and safety in refractory urticaria remain scarce. This study that adhered to the STROBE guidelines aims to systematically evaluate the sgAH-ranitidine combination as a potential novel therapeutic approach for refractory urticaria cases. Methods Patients This study recruited patients from the Department of Dermatology at Wuhan No. 1 Hospital. The inclusion criteria were as follows: (1) Age between 12 and 70 years; (2) CSU; (3) 2-fold doses treatment with sgAHs for ≥ 2 weeks still showed wheals and ithing frequently; (4) 7 days before inclusion: Weekly Urticaria Activity Score (UAS7) ≥ 7, Weekly Itch Severity Score (ISS7) ≥ 5. Exclusion criteria were as follows (If any one of the exclusion criteria is met, it is excluded): (1) The diagnosis included simple forms of induced urticaria, such as artificial urticaria, heat-induced urticaria, and cholinergic urticaria, etc; (2) Allergic to ranitidine or other bioanalogues, or a history of severe drug allergy or anaphylactic shock; (3) Any disease that may have symptoms of urticaria and/or angioedema, including: urticaria blood Angiitis, pigmented urticaria, erythema pleomorpha, mastocytosis, hereditary or acquired angioedema, lymphoma, leukemia, etc; (4) Have other chronic pruritus skin diseases that may affect the findings of the study, such as atopic dermatitis, bullous pemphigoid, herpetiform dermatitis, senile pruritus; (5) Screening for acute active infections requiring treatment, including but not limited to lung infections and tuberculosis; (6) Pregnant or lactating women; (7) The investigator determined that certain subjects had pre-existing conditions that rendered them unfit for participation in the study. The eligible population received treatment with ranitidine (300mg/day) while maintaining 2-fold dose of H1 receptor antagonists (H1RA) for a duration of 12 weeks. This study was conducted in accordance with the Declaration of Helsinki, the International Council for Harmonisation, and Good Clinical Practice. It received approval from the institutional review board or ethics committee at the study site. All patients provided written informed consent. For patients under 18 years of age, written informed consent was also obtained from their legal guardians. Assessments The primary endpoint was defined as the change in the UAS7 from baseline to week 12. The UAS7, a validated and widely adopted instrument for assessing urticaria severity, employs a dual-component evaluation system that independently quantifies both pruritus intensity and wheal formation using a 4-point Likert scale (0 = none to 3 = severe). The composite UAS7 score, derived from the summation of daily UAS measurements over seven consecutive days, yields a total score ranging from 0 to 42, where higher scores correspond to greater disease activity. Patients were classified as responders if their UAS7 score < 7. Another primary endpoint was the proportion of patients with Urticaria Control Test (UCT) score ≥ 12. UCT is a validated 4-item tool assessing chronic urticaria control. Each item is scored 0–4 (higher scores = better control), with a total range of 0–16. Scores ≥ 12 indicate well-controlled disease, while scores < 12 suggest inadequate control, potentially requiring treatment adjustment[ 18 , 19 ]. The partial responders were defined as individuals with a UAS7 score between 7 and 15, while nonresponders were those with a UAS7 score >15 [ 4 ]. A complete response was defined as a sustained UAS7 of 0, achieved with the use of a sgAHs plus ranitidine[ 4 , 18 , 19 ]. Secondary endpoints included the proportion of patients demonstrating a partial response, the number of patients with a UAS7 score of 0, and the proportion of patients with a UCT score of 16. Other secondary endpoints were ISS7 ≥ 5-point improvement from baseline to week12[ 20 ] and the improvement in Dermatology Life Quality Index (DLQI) scores from baseline[ 21 ]. Itch severity was assessed using a 10-cm visual analog scale (VAS), where 0 cm represented "no itch" and 10 cm indicated "worst imaginable itch." Daily pruritus severity was determined by recording the maximum VAS score each day, and the cumulative weekly score was calculated by summing the daily maximum scores over seven consecutive days, yielding a total score range of 0–70 cm, with higher values reflecting greater pruritus severity. DLQI is a validated instrument consisting of 10 items that assess health-related quality of life across six domains: symptoms and feelings, daily activities, leisure, work and school, personal relationships, and treatment. The total score, derived from the sum of all item responses, ranges from 0 to 30, where higher scores correspond to greater impairment in dermatology-specific quality of life. Corresponding laboratory tests were conducted on all patients. The incidence of AEs and SAEs during treatment was evaluated. Statistical analysis Continuous variables were presented as means and standard deviations (SD), or medians and inter quartile range (IQR) for variables with skewed distributions, and categorical variables as frequencies and percentages. Normal distribution was confirmed using the Shapiro-Wilk test or skewness and kurtosis. For bivariate analysis, the T-independent test and the Mann-Whitney test were used to compare parametric and nonparametric independent samples, respectively, whereas the Fisher exact test or the c2 test was used to evaluate associations between categorical variables. P values lower than 0.05 were considered statistically significant. Analyses were performed using SPSS software. Results Baseline characteristics A total of 33 patients were enrolled in the study, with a mean age of 41.5 ± 14.5 years. Before the addition of ranitidine, the median duration of urticaria was 60 days (IQR: 45–270 days), with a mean UAS7 of 24 ± 7.2 points and a mean UCT score of 6.4 ± 2.1 points(Table 1 , Fig. 1 ). Table 1 Baseline demographic and clinical characterization Baseline characteristic Value Total number of patients, n 33 Age, mean ± SD (y) 41.5 ± 14.5 Sex, female/male, n (%) 20(61)/13༈39༉ BMI, mean ± SD (kg/m2) 23.4 ± 3.6 Clinical manifestations Wheals, n (%) 28(85) Pruritus,n(%) 33(100) Erythema annularis, n (%) 5 (15) Dermographism, n (%) 14(42) Angioedema, n (%) 9 (27) CSU duration, median (IQR)(day) 60(45–270) UAS7 at baseline level, mean ± SD (points) 24 ± 7.2 UCT at baseline level, mean ± SD (points) 6.4 ± 2.1 Combined with Cholinergic urticaria, n (%) 3(9) Atopic diseases, n (%) 12(36) Family history of atopic diseases, n(%) 3(9) Drug allergies, n(%) 3(9) Previous therapy, n (%) sgAHs 33(100) One-generation H1-AH 4(12) Glucocorticoid 4(12) Other 5 (15) Abbreviations:SD, standard deviations; BMI, body mass index; CSU, chronic spontaneous urticaria; IQR, interquartile range; UAS7, urticaria activity score; UCT, Urticaria Control Test; sgAHs, second generation antihistamines. H1-AH, H1-antihistamines. Note: Atopic disease, contains history of urticaria (Acute or Chronic), Allergic rhinitis, Allergic conjunctivitis, Asthma; sgAHs, contains Loratadine, Ebastine, Desloratadine citrate, Cetirizine, Olopatadine, Epastine, Levocetirizine tablets; One-generation H1-AH，contains Ketotifen, Chlorpheniramine. Other, contains Compound glycyrrhizin tablets, Hydroxychloroquine, Vitamin C injection, Calcium gluconate injection, Antibiotic, Chinese herb. Table 2 Laboratory biomarkers’ baseline values of the study population Biomarker Value Total IgE (kU/L), median (IQR) (< 200 U/mL) 155 (52–225) CRP(ng/L), median (IQR) (<8 ng/L) 1.6 (0.1–4.5) ESR (mm), median (IQR) (< 15mm) 13 (5–20) D-dimer (mg/mL), median (IQR) ( 9 U/mL), n (%) 11/29 (38) Anti-TG (U/mL), mean ± SD (1.59–50.3 U/mL) 7.5 ± 4.8 FT3(Pmol/L), mean ± SD (3.53–7.37 Pmol/L) 5.4 ± 0.6 FT4(Pmol/L), median (IQR) (7.98–16.02 Pmol/L) 10.2(9.7–11.4) TSH(mIu/L), median (IQR) (0.56–5.91 mIu/L) 2(1.4–2.9) Vitamin-D(ng/ml), mean ± SD (20–100 ng/ml) 15.6 ± 6.9 Positive ASST,n(%) 11/24 (46) Abbreviations: IgE, immunoglobulin E; IQR, interquartile range; CRP, Creactive protein; ESR, Erythrocyte sedimentation rate; ANA, Antinuclear antibodies; Anti-TPO, antiethyroid peroxidase antibodies; Anti-TG, antithyroglobulin antibodies; SD, standard deviations; FT3, Free triiodothyronine; FT4, Free thyroxine; TSH, Thyroid stimulating hormone; ASST, Autologous serum skin test. A total of 33 patients were diagnosed with CSU, with 9 (27%) experiencing concomitant angioedema. Additionally, 3 patients (9%) complicated with cholinergic urticaria (CholU) and symptomatic dermographism (SD) was identified in 14(42%) patients. The majority of patients presented with wheals, while 5(15%) patients primarily exhibited erythema annulare. Corresponding laboratory tests were conducted on the enrolled patients. Primary Outcome At 12 weeks of treatment, the proportion of patients achieving a response is shown in Fig. 2 (a). The mean change in UCT scores for the combination drug therapy from baseline (mean score: 6.4 ± 2.1) to week 4 (mean score: 9.7 ± 3.8) was 3 points. The proportion of patients achieving disease control after treatment is shown in Fig. 2 (b). Secondary Outcomes By week 12, 6(18%) patients became partial responders and 6(18%) patients achieved a UAS7 score of 0, indicating a complete response to the combination drug therapy. 5(15%) patients had a UCT score of 16. The mean ISS7 score at baseline for all patients was 12 ± 4.5 points. At 12 weeks, the proportion of patients achieving an improvement of 5 points or greater in ISS7 is shown in Fig. 3 . Although some patients continued to experience wheals, the severity of itching symptoms was significantly reduced. However, the exact mechanism underlying this improvement remains unclear. Additionally, there were greater reductions in DLQI scores. The median baseline DLQI score was 3 points (IQR: 2–5 points). Over 75% of patients reported scoring only on the itch-related items. By week 12, the median DLQI score among patients had decreased to 1 point (IQR: 1–3 points). At week 12, the proportion of patients achieving a DLQI score of 0 or 1 is shown in Fig. 4 , reflecting a notable improvement in their quality of life. Correlation analysis of response group and nonresponse group A total of 33 outpatient cases was collected. Among these, 15 patients achieved disease control at the 12-week mark. The all participants were divided into two groups: response group (n = 15) and non-response group (n = 18). There were no significant differences in age, sex, Body mass index (BMI), or mean duration of the disease between the groups (P > 0.05)(Table 3 ). Table 3 Characteristics of the response group and nonresponse group Trial characteristics Response group (N = 15) Nonresponse group (N = 18) P-value Age, mean ± SD (y) 39.1 ± 14.7 43.2 ± 14.5 0.447 Sex, female/male, n (%) 10(67)/5(33) 10(56)/8(44) 0.440 BMI, mean ± SD (kg/m2) 24.1 ± 2.6 23.0 ± 4.2 0.427 Clinical manifestations Wheals, n (%) 14(93) 14(78) Pruritus,n(%) 15(100) 18(100) Erythema annularis, n (%) 1(7) 4(22) 0.368 Dermographism, n (%) 5(33) 9(50) 0.755 Angioedema, n (%) 3(20) 6(33) 0.696 CSU duration, median (IQR) (day) 60(45–143) 121(30–456) 0.748 UAS7 at baseline level, mean ± SD (points) 20.5 ± 7.4 26.4 ± 6.2 0.023 UCT at baseline level, mean ± SD (points) 6.9 ± 2.2 6.1 ± 1.9 0.336 Combined with Cholinergic urticaria, n (%) 3(20) 0 0.064 Atopic diseases, n (%) 5(33) 7(39) 0.981 Family history of atopic diseases,n(%) 0 3(17) 0.245 Drug allergies, n(%) 1(7) 2(11) 1.000 Positive ASST,n(%) 3/9(33) 8/15(53) 0.420 Total IgE(kU/L),median (IQR)(0.1–200 U/mL) 178.2(77.1–222.0) 148.0(39.3-330.5) 0.707 CRP(ng/L), median (IQR) (0–8 ng/L) 1.2(0.1-4.0) 1.9(0.1–5.8) 0.578 ESR (mm), median (IQR) (0-15mm) 14(5.5–20.5) 11(5.0-26.8) 0.775 D-dimer(mg/mL),median(IQR)(0-0.55mg/mL) 0(0–1) 0(0–1) 0.823 Positive ANA, n (%) 5/12(42) 7/17(41) 1.000 Anti-TPO (U/mL), median (IQR) (0-9U/mL) 1(0.3–38.3) 2.3(0.9–21.5) 0.626 Positive (> 9 U/mL), n (%) 5/12(42) 6/17(35) 1.000 Anti-TG (U/mL), mean ± SD (1.59-50.3U/mL) 8.0 ± 5.7 7.1 ± 4.3 0.638 FT3(Pmol/L), mean ± SD (3.53–7.37 Pmol/L) 5.4 ± 0.9 5.4 ± 0.4 0.891 FT4(Pmol/L),median(IQR) (7.98-16.02Pmol/L) 10.4(9.9–13.1) 10.1(9.6–10.9) 0.159 TSH(mIu/L), median (IQR) (0.56–5.91 mIu/L) 2.3(1.4-3.0) 1.9(1.4–2.7) 0.516 Vitamin-D(ng/ml), mean ± SD (20–100 ng/ml) 15.0 ± 5.3 16.0 ± 8.0 0.713 Abbreviations:SD, standard deviations; BMI, body mass index; CSU, chronic spontaneous urticaria; IQR, interquartile range; UAS7, urticaria activity score; UCT, Urticaria Control Test; sgAHs, second generation antihistamines. H1-AH, H1-antihistamines. IgE, immunoglobulin E; CRP, Creactive protein; ESR, Erythrocyte sedimentation rate; ANA, Antinuclear antibodies; Anti-TPO, antiethyroid peroxidase antibodies; Anti-TG, antithyroglobulin antibodies; FT3, Free triiodothyronine; FT4, Free thyroxine; TSH, Thyroid stimulating hormone; ASST, Autologous serum skin test. The proportion of patients with cyclic erythematous lesions, positive dermal scratch tests, positive ASST, and a prolonged course of disease was higher in the nonresponse group compared to the response group. What’s more, a higher baseline level of UAS7 was associated with a lower response rate to the antihistamine and ranitidine combination. This difference between the two subgroups was statistically significant (P < 0.05). These findings indicate that ranitidine may offer only limited benefit in patients with a prolonged disease course, a baseline UAS7 score <25, annular erythematous skin lesions, or those exhibiting positive dermal scratches or an ASST response. Adverse Effects Overall, the treatment was well tolerated, with adverse effects (AE) reported as minimal. During previous treatment with H1-AH, 4 (12%) patients reported experiencing somnolence. dizziness was observed in 1 (3%) patient, and dry mouth in 2 (6%) patients. Excluding the adverse effects associated with previous antihistamine use, 4 patients (12%) experienced mild adverse effects after the addition of ranitidine(Table 4 ). Table 4 Summary of AEs after the addition of ranitidine up to Week 12 AEs H1-AH plus ranitidine (N = 33) n(%) Patients with at least one AE 4 (12) Blurred vision 1 (3) Insomnia 1 (3) Abdominal pain 1 (3) Diarrhea 1 (3) Fatigue 1 (3) None of the patients discontinued treatment due to AEs. Furthermore, no clinically relevant abnormalities were observed in clinical laboratory or vital sign assessments for any patients undergoing treatment. Discussion The presence of two distinct classes of H1 histamine receptors and H2-histamine receptors, (H1RAs、H2RAs) in the skin has been well established for some time. These receptors play a significant role in the pathogenesis of urticaria[ 22 ]. The precise mode of action of H2RAs remains somewhat uncertain. Previous studies have demonstrated that several H1RAs and H2RAs, now reclassified as inverse agonists, have been effectively used in clinical settings to achieve the desired therapeutic outcomes, despite the occurrence of side effects. The concept of inverse agonism emerged from experimental observations indicating that certain drugs can decrease the activity of receptor systems that are active even in the absence of agonists. These ligands preferentially bind to and stabilize the inactive conformation of the receptors. However, it remains unclear whether inverse agonism is essential or significant for these drugs to exert their therapeutic effects[ 23 ]. Histamine is a potent mediator of immediate hypersensitivity reactions. Approximately 15% of the histamine receptors in the skin are H2 receptors (H2R), and it is well established that human skin mast cells, which store histamine, also express H2R. H2RAs are reversible structural analogs of histamine, characterized by slightly altered chemical structures, that reduce the tonic activation rate of the receptor[ 22 ]. These agents function as inverse agonists, binding to the same receptor sites as agonists and reversing receptor activity, which results in a functional antagonism of histamine. Consequently, they reduce histamine activity at the receptor sites. By doing so, these agents may inhibit histamine release and mitigate or even prevent the symptoms of urticaria[ 23 ]. Ranitidine, a histamine H2-receptor antagonist (H2RA), has been the subject of recent investigations concerning its potential toxicity and N-nitrosodimethylamine (NDMA) contamination. Current research provides relatively conclusive evidence that no significant positive correlation exists between ranitidine use and cancer incidence rates across multiple national populations. Furthermore, comparative analyses reveal no statistically significant difference in cancer risk between ranitidine users and other H2RA users [ 24 , 25 ]. Recent studies have conducted systematic analyses to evaluate the potential formation of NDMA from ranitidine under simulated physiological conditions. Experimental models replicating gastrointestinal tract environments and systemic circulation parameters revealed that ranitidine exhibits negligible conversion to NDMA in both intestinal and blood compartments. This conclusion remains valid even under supplementary exposure to chloraminated tap water (containing monochloramine, NH₂Cl) at concentrations reflecting typical municipal water treatment levels. The findings suggest that physiological pH, enzymatic activity, and redox homeostasis collectively constitute effective biochemical barriers against NDMA generation from ranitidine in vivo[ 26 – 29 ]. In certain underdeveloped regions and countries where access to omalizumab is limited, alternative treatment options for refractory CSU are required. Notably, ranitidine remains one of the recommended alternative agents in European urticaria treatment guidelines[ 10 ]. The appropriate and moderate use of ranitidine may offer greater benefits than risks for certain patients with refractory CSU. In this study, we included a total of 33 patients with CU. Among these patients, total IgE levels were abnormally elevated in 11/29 (38%) cases, while Antinuclear antibodies (ANA) tested positive in 12/29 (41%) patients. Additionally, antiethyroid peroxidase antibodies (anti-TPO) antibody levels were elevated in 11/29 (38%) patients, and 24/29 (83%) exhibited insufficient levels of vitamin D. These findings are consistent with previous studies, which suggest that patients with anti-ANA and TPO-positive urticaria are more likely to exhibit resistance to conventional antihistamines[ 30 ]. Urticaria patients are more likely to develop vitamin D deficiency, which is consistent with previously reported findings [ 31 ]. In our cohort, 15 (45%) patients achieved disease control following treatment with double the standard doses of sgAHs combined with ranitidine. Based on this outcome, we categorized the participants into two groups: the response group and the nonresponse group. In the nonresponse group, 4 (22%) patients presented with annular erythematous lesions, a significantly higher proportion than that observed in the response group. This finding suggests that patients with urticaria characterized by annular or semi-annular lesions may be less responsive to treatment with ranitidine. However, research on specific types of urticaria remains limited. CU can be classified into two categories based on its underlying causes: CSU and chronic induced urticaria (CIndU)[ 32 ]. Induced urticaria includes various types, such as SD and CholU, among others [ 1 , 33 – 35 ]. SD is the most prevalent form of CIndU. Many patients report experiencing chronic pruritus characterized as "a crawling sensation" on the skin, often without a visible rash. This discomfort can lead to scratching and the development of linear wheals. Currently, the effectiveness of available treatment options for patients with SD remains largely uncertain[ 35 ]. Indeed, CIndU is a common comorbidity in patients with antihistamine-refractory CSU, affecting approximately 24% of this population[ 36 ]. In the studied population, we observed a significant reduction in the incidence of wheals in some patients after 4 weeks of treatment; however, itching persisted. In the nonresponse group, the proportion of patients with dermographism was higher than that in the response group. We concluded that ranitidine may be less effective in patients with dermographism. In contrast, the proportion of CSU patients with CholU was 20% in the response group and 0% in the nonresponse group. It has been reported that the addition of a H2RAs can be effective for patients with refractory CholU who do not respond to increased dosing of an H1RAs. However, there is limited information regarding the specific CholU subtype [ 33 ]. These results suggest that ranitidine is more effective in patients with cholinergic urticaria than in those with other forms of induced urticaria. Although the pathogenesis of CSU is not yet fully understood, it is well established that the signs and symptoms result from the activation of skin mast cells and the subsequent release of their mediators[ 8 ]. Recent evidence indicates that the causes of CSU include Type I autoimmunity (CSUaiTI) and Type IIb autoimmunity (CSUaiTIIb). Basic test results in CSU can help differentiate between CSUaiTI and CSUaiTIIb, with elevated CRP levels more frequently observed in CSUaiTI, while eosinophil and basophil counts are often reduced in CSUaiTIIb. Testing for IgG anti-TPO antibodies and total IgE levels are essential basic tests that should be conducted in CSU patients under specialist care to provide greater clarity regarding their condition. CSUaiTIIb is characterized by increased disease severity, the presence of concomitant autoimmune diseases, low total IgE levels, elevated IgG anti-TPO levels, basopenia, eosinopenia, poor response to antihistamines and omalizumab, and a favorable response to cyclosporine[ 8 ]. Currently, a high ratio of IgG anti-TPO to total IgE is considered the best surrogate marker for CSUaiTIIb[ 8 , 37 ]. The literature also suggests that the Autologous serum skin test (ASST) may serve as a potential marker for CSUaiTIIb, alongside the direct detection of IgE and FcεRI autoantibodies. In our study, 53% of patients in the nonresponse treatment group had a positive ASST, higher than the 33% observed in the responsee treatment group. The results indicate that patients with a positive ASST are more likely to be non-responders to ranitidine treatment. Additionally, in the nonresponse group, a higher proportion of ASST-positive patients exhibited low total IgE levels, aligning with previous research findings. However, we did not observe ASST-positive patients with elevated anti-TPO antibody levels. Further validation may require studies with larger sample sizes. Previous studies have suggested that elevated D-dimer levels may indicate that urticaria patients are poor response to H1-AH therapy[ 38 ]. In this trial, 41% (7/17) of patients in the nonresponse group had elevated D-dimer levels, which was higher than that of the response group (33%, 4/12). Additionally, a prior study reported significantly higher rates of positive ASST results, skin scratch test outcomes, and longer disease durations in patients with high total IgE levels compared to those with low total IgE[ 39 ]. Nonetheless, our research did not find a statistically significant difference in these parameters (P > 0.05). Our clinical study demonstrated that moderate-dose ranitidine (300 mg/day) effectively controlled urticarial lesions, significantly reduced ISS7 scores (ISS7 improvement ≥ 5 points in 64% of patients), and improved quality-of-life metrics of CSU patient (achieved a DLQI score of 0 or 1 in 58% of patients). No grade 3–4 adverse events were recorded during the 12-week follow-up period, indicating an acceptable safety profile. These preliminary results suggest a clinically meaningful risk-benefit ratio for this patient subgroup. Nevertheless, the single-center design, limited cohort size (n = 33), and intermediate-term observation period necessitate larger multicenter trials with extended follow-up to establish the long-term efficacy and safety of ranitidine in refractory CSU management. Conclusions In CSU patients with a short disease duration, a baseline UAS7 score < 25, skin lesions characterized by wind masses, no skin scratches, and a negative ASST, as well as in those with concomitant cholinergic urticaria, the addition of ranitidine may improve the disease response rate. No serious adverse reactions were observed after the addition of ranitidine, and the treatment was well tolerated. This combination can serve as an alternative treatment option for patients with refractory urticaria. Declarations Conflict of Interest : The authors declare that they have no conflict of interest. Ethical Approval: This study was approved by the Research Ethics Committee of Wuhan No.1 Hospital and conformed to the Declaration of Helsinki.[2023]53. Funding information: This work was supported by the Natural Science Foundation of HuBei Province (grant number: 2023AFB1072) Author Contribution Data curation and writing of the original draft: Zhou Yu, Wang Bei, Li Xinyu; Conceptualization and Methodology: Kai Chen, Jiang Ruili, Qu Zilu; Writing review and editing, supervision, and funding acquisition: Chen Liuqing, Hu Feng. Acknowledgements: We extend our heartfelt gratitude to all the patients who participated in this study. Data availability statement: The datasets generated and analyzed during the current study are not publicly available due to privacy issues. 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1","display":"","copyAsset":false,"role":"figure","size":27209,"visible":true,"origin":"","legend":"\u003cp\u003ePatient disposition\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-7241257/v1/4ef144fa99a08798f81adb9a.png"},{"id":93238620,"identity":"d80c6901-aa97-4706-871d-61a23f4e3b0f","added_by":"auto","created_at":"2025-10-10 14:35:11","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":96252,"visible":true,"origin":"","legend":"\u003cp\u003eThe proportion of patients achieving response and ultimate disease control\u003c/p\u003e\n\u003cp\u003eThe proportion of patients achieving response and ultimate disease control. (a) By week 4, 13 patients (39%) had become responders, with no significant differences observed between patients with and without angioedema. The proportion of patients responding to the addition of ranitidine to H1-antihistamine therapy shows an increasing trend. By week 12, the median UAS7 for all patients was 12 points (IQR: 2–25 points), with 16 patients classified as responders. (b) By week 12, 15 patients (45%) had achieved disease control.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-7241257/v1/d2f08b5d0a0402d6147a01a2.png"},{"id":93240100,"identity":"7f5d7163-cf05-43d7-9433-cfb0140d7402","added_by":"auto","created_at":"2025-10-10 14:43:11","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":13002,"visible":true,"origin":"","legend":"\u003cp\u003eProportion of patients with ISS7≥5-point improvement at Week 12\u003c/p\u003e\n\u003cp\u003eAt 12 weeks, 64% of patients had an ISS7 score of 5 or higher compared to baseline, and 58% of patients reported an improvement in pruritus after one week of treatment.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-7241257/v1/ce7e8f5000bf126c4df23541.png"},{"id":93238618,"identity":"b2c6a539-0e92-498f-8f4b-f9cff55163c0","added_by":"auto","created_at":"2025-10-10 14:35:11","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":12607,"visible":true,"origin":"","legend":"\u003cp\u003eProportion of patients with DLQI 0/1 at Week 12\u003c/p\u003e\n\u003cp\u003eAt 12 weeks the propotion of DLQI 0/1 was 58%.\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-7241257/v1/3a7b16569e1eb4f250277904.png"},{"id":101753341,"identity":"311afd0d-a1d5-4aae-b947-ccddb10c2854","added_by":"auto","created_at":"2026-02-03 10:39:46","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":887462,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7241257/v1/aec76cc5-e284-44c4-bf3d-257c7ebaa621.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Safety and efficacy of h1-antihistamines plus ranitidine in refractory Chronic Spontaneous Urticaria","fulltext":[{"header":"Introduction","content":"\u003cp\u003eUrticaria is a common, heterogeneous inflammatory skin disorder characterized by recurrent pruritic wheals, angioedema, or both [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. With a lifetime prevalence reaching 20%[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e], chronic urticaria (CU)—defined as symptoms persisting for \u0026gt; 6 weeks—manifests as spontaneous wheals with or without angioedema, irrespective of inducible triggers[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Globally, CU affects 0.5–1% of the population, typically lasting 1–5 years. [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e] This condition imposes substantial patient and societal burdens, severely compromising quality of life (QoL)[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Treatment responses exhibit marked interindividual variability, reflecting the disease's clinical heterogeneity[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Current guidelines recommend second-generation H1-antihistamines (sgAHs) at standard doses as first-line therapy for chronic spontaneous urticaria (CSU)[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. While approximately 50% of CU patients respond to sgAHs[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e], those with inadequate symptom control after 2–4 weeks (or earlier if symptoms are severe) may receive up to 4-fold dose escalation[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. For patients unresponsive to maximized antihistamine therapy, omalizumab is recommended as second-line add-on treatment[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Cyclosporine is reserved as third-line therapy exclusively for severe, refractory cases failing combined antihistamine and omalizumab treatment[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e], though its use is limited by significant safety concerns [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eOmalizumab, a recombinant humanized monoclonal anti-IgE antibody, is an approved treatment for CSU[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Randomized controlled trial evidence demonstrates that nearly 50% of patients still experience persistent wheals and pruritus despite 4-fold increased antihistamine doses, requiring biologic intervention with omalizumab[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. The optimal dosing regimen is well-established in current guidelines[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. While licensed omalizumab doses show efficacy in H1-antihistamine-refractory CSU, approximately 30% of patients remain symptomatic after ≥ 6 months of therapy[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Despite proven efficacy, omalizumab's widespread adoption faces multiple socioeconomic and systemic barriers. Its substantially higher cost relative to conventional antihistamines, combined with variable reimbursement policies and restrictive eligibility criteria, creates significant access challenges for refractory urticaria patients[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Global availability shows marked geographical disparities, with particularly limited access in resource-limited settings. Furthermore, treatment-emergent hypersensitivity reactions and other adverse events may further constrain its clinical utility.The suboptimal response observed in some patients remains multifactorial, necessitating further research to optimize therapeutic strategies for this population. Meanwhile, clinical studies have investigated alternative approaches, including H1-antihistamine combination therapies[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eIn clinical practice, sgAHs combined with ranitidine are commonly used to treat urticaria. Previous studies have shown improved response rates with ranitidine combination therapy in acute urticaria[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Notably, Ogawa et al.'s retrospective study demonstrated higher remission rates in H1-antihistamine-resistant chronic urticaria patients receiving adjunctive H2-antihistamine (ranitidine) therapy[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. However, robust clinical data on this combination's efficacy and safety in refractory urticaria remain scarce. This study that adhered to the STROBE guidelines aims to systematically evaluate the sgAH-ranitidine combination as a potential novel therapeutic approach for refractory urticaria cases.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e\u003cb\u003ePatients\u003c/b\u003e\u003c/p\u003e\u003cp\u003eThis study recruited patients from the Department of Dermatology at Wuhan No. 1 Hospital. The inclusion criteria were as follows: (1) Age between 12 and 70 years; (2) CSU; (3) 2-fold doses treatment with sgAHs for ≥ 2 weeks still showed wheals and ithing frequently; (4) 7 days before inclusion: Weekly Urticaria Activity Score (UAS7) ≥ 7, Weekly Itch Severity Score (ISS7) ≥ 5. Exclusion criteria were as follows (If any one of the exclusion criteria is met, it is excluded): (1) The diagnosis included simple forms of induced urticaria, such as artificial urticaria, heat-induced urticaria, and cholinergic urticaria, etc; (2) Allergic to ranitidine or other bioanalogues, or a history of severe drug allergy or anaphylactic shock; (3) Any disease that may have symptoms of urticaria and/or angioedema, including: urticaria blood Angiitis, pigmented urticaria, erythema pleomorpha, mastocytosis, hereditary or acquired angioedema, lymphoma, leukemia, etc; (4) Have other chronic pruritus skin diseases that may affect the findings of the study, such as atopic dermatitis, bullous pemphigoid, herpetiform dermatitis, senile pruritus; (5) Screening for acute active infections requiring treatment, including but not limited to lung infections and tuberculosis; (6) Pregnant or lactating women; (7) The investigator determined that certain subjects had pre-existing conditions that rendered them unfit for participation in the study. The eligible population received treatment with ranitidine (300mg/day) while maintaining 2-fold dose of H1 receptor antagonists (H1RA) for a duration of 12 weeks.\u003c/p\u003e\u003cp\u003e This study was conducted in accordance with the Declaration of Helsinki, the International Council for Harmonisation, and Good Clinical Practice. It received approval from the institutional review board or ethics committee at the study site. All patients provided written informed consent. For patients under 18 years of age, written informed consent was also obtained from their legal guardians.\u003c/p\u003e\u003cp\u003e\u003cb\u003eAssessments\u003c/b\u003e\u003c/p\u003e\u003cp\u003eThe primary endpoint was defined as the change in the UAS7 from baseline to week 12. The UAS7, a validated and widely adopted instrument for assessing urticaria severity, employs a dual-component evaluation system that independently quantifies both pruritus intensity and wheal formation using a 4-point Likert scale (0 = none to 3 = severe). The composite UAS7 score, derived from the summation of daily UAS measurements over seven consecutive days, yields a total score ranging from 0 to 42, where higher scores correspond to greater disease activity. Patients were classified as responders if their UAS7 score \u0026lt; 7. Another primary endpoint was the proportion of patients with Urticaria Control Test (UCT) score ≥ 12. UCT is a validated 4-item tool assessing chronic urticaria control. Each item is scored 0–4 (higher scores = better control), with a total range of 0–16. Scores ≥ 12 indicate well-controlled disease, while scores \u0026lt; 12 suggest inadequate control, potentially requiring treatment adjustment[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eThe partial responders were defined as individuals with a UAS7 score between 7 and 15, while nonresponders were those with a UAS7 score \u0026gt;15 [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. A complete response was defined as a sustained UAS7 of 0, achieved with the use of a sgAHs plus ranitidine[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eSecondary endpoints included the proportion of patients demonstrating a partial response, the number of patients with a UAS7 score of 0, and the proportion of patients with a UCT score of 16. Other secondary endpoints were ISS7 ≥ 5-point improvement from baseline to week12[\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e] and the improvement in Dermatology Life Quality Index (DLQI) scores from baseline[\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. Itch severity was assessed using a 10-cm visual analog scale (VAS), where 0 cm represented \"no itch\" and 10 cm indicated \"worst imaginable itch.\" Daily pruritus severity was determined by recording the maximum VAS score each day, and the cumulative weekly score was calculated by summing the daily maximum scores over seven consecutive days, yielding a total score range of 0–70 cm, with higher values reflecting greater pruritus severity. DLQI is a validated instrument consisting of 10 items that assess health-related quality of life across six domains: symptoms and feelings, daily activities, leisure, work and school, personal relationships, and treatment. The total score, derived from the sum of all item responses, ranges from 0 to 30, where higher scores correspond to greater impairment in dermatology-specific quality of life. Corresponding laboratory tests were conducted on all patients. The incidence of AEs and SAEs during treatment was evaluated.\u003c/p\u003e\u003ch2\u003eStatistical analysis\u003c/h2\u003e\u003cp\u003eContinuous variables were presented as means and standard deviations (SD), or medians and inter quartile range (IQR) for variables with skewed distributions, and categorical variables as frequencies and percentages. Normal distribution was confirmed using the Shapiro-Wilk test or skewness and kurtosis. For bivariate analysis, the T-independent test and the Mann-Whitney test were used to compare parametric and nonparametric independent samples, respectively, whereas the Fisher exact test or the c2 test was used to evaluate associations between categorical variables. P values lower than 0.05 were considered statistically significant. Analyses were performed using SPSS software.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003eBaseline characteristics\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA total of 33 patients were enrolled in the study, with a mean age of 41.5\u0026thinsp;\u0026plusmn;\u0026thinsp;14.5 years. Before the addition of ranitidine, the median duration of urticaria was 60 days (IQR: 45\u0026ndash;270 days), with a mean UAS7 of 24\u0026thinsp;\u0026plusmn;\u0026thinsp;7.2 points and a mean UCT score of 6.4\u0026thinsp;\u0026plusmn;\u0026thinsp;2.1 points(Table \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e, Fig. \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n \u003ctable id=\"Tab1\" border=\"1\" class=\"fr-table-selection-hover\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eBaseline demographic and clinical characterization\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eBaseline characteristic\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eValue\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTotal number of patients, n\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e33\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAge, mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD (y)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e41.5\u0026thinsp;\u0026plusmn;\u0026thinsp;14.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"1\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSex, female/male, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e20(61)/13༈39༉\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBMI, mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD (kg/m2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e23.4\u0026thinsp;\u0026plusmn;\u0026thinsp;3.6\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eClinical manifestations\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eWheals, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e28(85)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePruritus,n(%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e33(100)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eErythema annularis, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e5 (15)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDermographism, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e14(42)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAngioedema, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e9 (27)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCSU duration, median (IQR)(day)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e60(45\u0026ndash;270)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eUAS7 at baseline level, mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD (points)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e24\u0026thinsp;\u0026plusmn;\u0026thinsp;7.2\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eUCT at baseline level, mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD (points)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e6.4\u0026thinsp;\u0026plusmn;\u0026thinsp;2.1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCombined with Cholinergic urticaria, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e3(9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAtopic diseases, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e12(36)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eFamily history of atopic diseases, n(%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e3(9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDrug allergies, n(%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e3(9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePrevious therapy, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003esgAHs\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e33(100)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eOne-generation H1-AH\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e4(12)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eGlucocorticoid\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e4(12)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eOther\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e5 (15)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003ctfoot\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"3\"\u003eAbbreviations:SD, standard deviations; BMI, body mass index; CSU, chronic spontaneous urticaria; IQR, interquartile range; UAS7, urticaria activity score; UCT, Urticaria Control Test; sgAHs, second generation antihistamines. H1-AH, H1-antihistamines.\u003cbr\u003eNote: Atopic disease, contains history of urticaria (Acute or Chronic), Allergic rhinitis, Allergic conjunctivitis, Asthma; sgAHs, contains Loratadine, Ebastine, Desloratadine citrate, Cetirizine, Olopatadine, Epastine, Levocetirizine tablets; One-generation H1-AH，contains Ketotifen, Chlorpheniramine. Other, contains Compound glycyrrhizin tablets, Hydroxychloroquine, Vitamin C injection, Calcium gluconate injection, Antibiotic, Chinese herb.\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tfoot\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n \u003cdiv align=\"left\" class=\"colspec\"\u003e\u003cbr\u003e\u003c/div\u003e\n \u003cdiv align=\"left\" class=\"colspec\"\u003e\u003cbr\u003e\u003c/div\u003e\n \u003ctable id=\"Tab2\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eLaboratory biomarkers\u0026rsquo; baseline values of the study population\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eBiomarker\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eValue\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTotal IgE (kU/L), median (IQR) (\u0026lt;\u0026thinsp;200 U/mL)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e155 (52\u0026ndash;225)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCRP(ng/L), median (IQR) (\u0026lt;8 ng/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.6 (0.1\u0026ndash;4.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eESR (mm), median (IQR) (\u0026lt;\u0026thinsp;15mm)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e13 (5\u0026ndash;20)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eD-dimer (mg/mL), median (IQR) (\u0026lt;\u0026thinsp;0.55 mg/mL)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.4 (0.2\u0026ndash;0.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePositive ANA, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e12/29 (41)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAnti-TPO (U/mL), median (IQR) (0\u0026ndash;9 U/mL)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2.1(0.6\u0026ndash;30.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePositive (\u0026gt;\u0026thinsp;9 U/mL), n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e11/29 (38)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAnti-TG (U/mL), mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD (1.59\u0026ndash;50.3 U/mL)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7.5\u0026thinsp;\u0026plusmn;\u0026thinsp;4.8\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eFT3(Pmol/L), mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD (3.53\u0026ndash;7.37 Pmol/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5.4\u0026thinsp;\u0026plusmn;\u0026thinsp;0.6\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eFT4(Pmol/L), median (IQR) (7.98\u0026ndash;16.02 Pmol/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10.2(9.7\u0026ndash;11.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTSH(mIu/L), median (IQR) (0.56\u0026ndash;5.91 mIu/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2(1.4\u0026ndash;2.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eVitamin-D(ng/ml), mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD (20\u0026ndash;100 ng/ml)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e15.6\u0026thinsp;\u0026plusmn;\u0026thinsp;6.9\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePositive ASST,n(%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e11/24 (46)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003ctfoot\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\"\u003eAbbreviations: IgE, immunoglobulin E; IQR, interquartile range; CRP, Creactive protein; ESR, Erythrocyte sedimentation rate; ANA, Antinuclear antibodies; Anti-TPO, antiethyroid peroxidase antibodies; Anti-TG, antithyroglobulin antibodies; SD, standard deviations; FT3, Free triiodothyronine; FT4, Free thyroxine; TSH, Thyroid stimulating hormone; ASST, Autologous serum skin test.\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tfoot\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n\u003cp\u003eA total of 33 patients were diagnosed with CSU, with 9 (27%) experiencing concomitant angioedema. Additionally, 3 patients (9%) complicated with cholinergic urticaria (CholU) and symptomatic dermographism (SD) was identified in 14(42%) patients. The majority of patients presented with wheals, while 5(15%) patients primarily exhibited erythema annulare. Corresponding laboratory tests were conducted on the enrolled patients.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePrimary Outcome\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAt 12 weeks of treatment, the proportion of patients achieving a response is shown in Fig. \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e(a).\u003c/p\u003e\n\u003cp\u003eThe mean change in UCT scores for the combination drug therapy from baseline (mean score: 6.4\u0026thinsp;\u0026plusmn;\u0026thinsp;2.1) to week 4 (mean score: 9.7\u0026thinsp;\u0026plusmn;\u0026thinsp;3.8) was 3 points. The proportion of patients achieving disease control after treatment is shown in Fig. \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e(b).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSecondary Outcomes\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eBy week 12, 6(18%) patients became partial responders and 6(18%) patients achieved a UAS7 score of 0, indicating a complete response to the combination drug therapy. 5(15%) patients had a UCT score of 16.\u003c/p\u003e\n\u003cp\u003eThe mean ISS7 score at baseline for all patients was 12\u0026thinsp;\u0026plusmn;\u0026thinsp;4.5 points. At 12 weeks, the proportion of patients achieving an improvement of 5 points or greater in ISS7 is shown in Fig. \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e. Although some patients continued to experience wheals, the severity of itching symptoms was significantly reduced. However, the exact mechanism underlying this improvement remains unclear. Additionally, there were greater reductions in DLQI scores. The median baseline DLQI score was 3 points (IQR: 2\u0026ndash;5 points). Over 75% of patients reported scoring only on the itch-related items. By week 12, the median DLQI score among patients had decreased to 1 point (IQR: 1\u0026ndash;3 points). At week 12, the proportion of patients achieving a DLQI score of 0 or 1 is shown in Fig. \u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e, reflecting a notable improvement in their quality of life.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCorrelation analysis of response group and nonresponse group\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA total of 33 outpatient cases was collected. Among these, 15 patients achieved disease control at the 12-week mark. The all participants were divided into two groups: response group (n\u0026thinsp;=\u0026thinsp;15) and non-response group (n\u0026thinsp;=\u0026thinsp;18). There were no significant differences in age, sex, Body mass index (BMI), or mean duration of the disease between the groups (P\u0026thinsp;\u0026gt;\u0026thinsp;0.05)(Table \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n \u003cdiv align=\"left\" class=\"colspec\"\u003e\u003cbr\u003e\u003c/div\u003e\n \u003cdiv align=\"left\" class=\"colspec\"\u003e\u003cbr\u003e\u003c/div\u003e\n \u003cdiv align=\"left\" class=\"colspec\"\u003e\u003cbr\u003e\u003c/div\u003e\n \u003cdiv align=\"left\" class=\"colspec\"\u003e\u003cbr\u003e\u003c/div\u003e\n \u003ctable id=\"Tab3\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eCharacteristics of the response group and nonresponse group\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eTrial characteristics\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eResponse\u003c/p\u003e\n \u003cp\u003egroup\u003c/p\u003e\n \u003cp\u003e(N\u0026thinsp;=\u0026thinsp;15)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eNonresponse\u003c/p\u003e\n \u003cp\u003egroup\u003c/p\u003e\n \u003cp\u003e(N\u0026thinsp;=\u0026thinsp;18)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eP-value\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAge, mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD (y)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e39.1\u0026thinsp;\u0026plusmn;\u0026thinsp;14.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e43.2\u0026thinsp;\u0026plusmn;\u0026thinsp;14.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.447\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSex, female/male, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10(67)/5(33)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10(56)/8(44)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.440\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBMI, mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD (kg/m2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e24.1\u0026thinsp;\u0026plusmn;\u0026thinsp;2.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e23.0\u0026thinsp;\u0026plusmn;\u0026thinsp;4.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.427\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eClinical manifestations\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eWheals, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e14(93)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e14(78)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePruritus,n(%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e15(100)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e18(100)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eErythema annularis, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1(7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4(22)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.368\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDermographism, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5(33)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e9(50)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.755\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAngioedema, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3(20)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6(33)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.696\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCSU duration, median (IQR) (day)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e60(45\u0026ndash;143)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e121(30\u0026ndash;456)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.748\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eUAS7 at baseline level, mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD (points)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e20.5\u0026thinsp;\u0026plusmn;\u0026thinsp;7.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e26.4\u0026thinsp;\u0026plusmn;\u0026thinsp;6.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.023\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eUCT at baseline level, mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD (points)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6.9\u0026thinsp;\u0026plusmn;\u0026thinsp;2.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6.1\u0026thinsp;\u0026plusmn;\u0026thinsp;1.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.336\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCombined with Cholinergic urticaria, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3(20)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.064\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAtopic diseases, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5(33)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7(39)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.981\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eFamily history of atopic diseases,n(%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3(17)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.245\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDrug allergies, n(%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1(7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2(11)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.000\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePositive ASST,n(%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3/9(33)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8/15(53)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.420\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTotal IgE(kU/L),median (IQR)(0.1\u0026ndash;200 U/mL)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e178.2(77.1\u0026ndash;222.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e148.0(39.3-330.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.707\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCRP(ng/L), median (IQR) (0\u0026ndash;8 ng/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.2(0.1-4.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.9(0.1\u0026ndash;5.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.578\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eESR (mm), median (IQR) (0-15mm)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e14(5.5\u0026ndash;20.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e11(5.0-26.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.775\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eD-dimer(mg/mL),median(IQR)(0-0.55mg/mL)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0(0\u0026ndash;1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0(0\u0026ndash;1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.823\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePositive ANA, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5/12(42)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7/17(41)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.000\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAnti-TPO (U/mL), median (IQR) (0-9U/mL)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1(0.3\u0026ndash;38.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2.3(0.9\u0026ndash;21.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.626\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePositive (\u0026gt;\u0026thinsp;9 U/mL), n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5/12(42)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6/17(35)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.000\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAnti-TG (U/mL), mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD (1.59-50.3U/mL)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8.0\u0026thinsp;\u0026plusmn;\u0026thinsp;5.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7.1\u0026thinsp;\u0026plusmn;\u0026thinsp;4.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.638\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eFT3(Pmol/L), mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD (3.53\u0026ndash;7.37 Pmol/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5.4\u0026thinsp;\u0026plusmn;\u0026thinsp;0.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5.4\u0026thinsp;\u0026plusmn;\u0026thinsp;0.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.891\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eFT4(Pmol/L),median(IQR) (7.98-16.02Pmol/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10.4(9.9\u0026ndash;13.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10.1(9.6\u0026ndash;10.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.159\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTSH(mIu/L), median (IQR) (0.56\u0026ndash;5.91 mIu/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2.3(1.4-3.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.9(1.4\u0026ndash;2.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.516\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eVitamin-D(ng/ml), mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD (20\u0026ndash;100 ng/ml)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e15.0\u0026thinsp;\u0026plusmn;\u0026thinsp;5.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e16.0\u0026thinsp;\u0026plusmn;\u0026thinsp;8.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.713\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003ctfoot\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\"\u003eAbbreviations:SD, standard deviations; BMI, body mass index; CSU, chronic spontaneous urticaria; IQR, interquartile range; UAS7, urticaria activity score; UCT, Urticaria Control Test; sgAHs, second generation antihistamines. H1-AH, H1-antihistamines. IgE, immunoglobulin E; CRP, Creactive protein; ESR, Erythrocyte sedimentation rate; ANA, Antinuclear antibodies; Anti-TPO, antiethyroid peroxidase antibodies; Anti-TG, antithyroglobulin antibodies; FT3, Free triiodothyronine; FT4, Free thyroxine; TSH, Thyroid stimulating hormone; ASST, Autologous serum skin test.\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tfoot\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n\u003cp\u003eThe proportion of patients with cyclic erythematous lesions, positive dermal scratch tests, positive ASST, and a prolonged course of disease was higher in the nonresponse group compared to the response group. What\u0026rsquo;s more, a higher baseline level of UAS7 was associated with a lower response rate to the antihistamine and ranitidine combination. This difference between the two subgroups was statistically significant (P\u0026thinsp;\u0026lt;\u0026thinsp;0.05). These findings indicate that ranitidine may offer only limited benefit in patients with a prolonged disease course, a baseline UAS7 score \u0026lt;25, annular erythematous skin lesions, or those exhibiting positive dermal scratches or an ASST response.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAdverse Effects\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOverall, the treatment was well tolerated, with adverse effects (AE) reported as minimal. During previous treatment with H1-AH, 4 (12%) patients reported experiencing somnolence. dizziness was observed in 1 (3%) patient, and dry mouth in 2 (6%) patients. Excluding the adverse effects associated with previous antihistamine use, 4 patients (12%) experienced mild adverse effects after the addition of ranitidine(Table \u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n \u003cdiv align=\"left\" class=\"colspec\"\u003e\u003cbr\u003e\u003c/div\u003e\n \u003cdiv align=\"left\" class=\"colspec\"\u003e\u003cbr\u003e\u003c/div\u003e\n \u003ctable id=\"Tab4\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eSummary of AEs after the addition of ranitidine up to Week 12\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eAEs\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eH1-AH plus ranitidine\u003c/p\u003e\n \u003cp\u003e(N\u0026thinsp;=\u0026thinsp;33)\u003c/p\u003e\n \u003cp\u003en(%)\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePatients with at least one AE\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4 (12)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBlurred vision\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (3)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eInsomnia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (3)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAbdominal pain\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (3)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDiarrhea\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (3)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eFatigue\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (3)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n\u003cp\u003eNone of the patients discontinued treatment due to AEs. Furthermore, no clinically relevant abnormalities were observed in clinical laboratory or vital sign assessments for any patients undergoing treatment.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe presence of two distinct classes of H1 histamine receptors and H2-histamine receptors, (H1RAs、H2RAs) in the skin has been well established for some time. These receptors play a significant role in the pathogenesis of urticaria[\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. The precise mode of action of H2RAs remains somewhat uncertain. Previous studies have demonstrated that several H1RAs and H2RAs, now reclassified as inverse agonists, have been effectively used in clinical settings to achieve the desired therapeutic outcomes, despite the occurrence of side effects. The concept of inverse agonism emerged from experimental observations indicating that certain drugs can decrease the activity of receptor systems that are active even in the absence of agonists. These ligands preferentially bind to and stabilize the inactive conformation of the receptors. However, it remains unclear whether inverse agonism is essential or significant for these drugs to exert their therapeutic effects[\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. Histamine is a potent mediator of immediate hypersensitivity reactions. Approximately 15% of the histamine receptors in the skin are H2 receptors (H2R), and it is well established that human skin mast cells, which store histamine, also express H2R. H2RAs are reversible structural analogs of histamine, characterized by slightly altered chemical structures, that reduce the tonic activation rate of the receptor[\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. These agents function as inverse agonists, binding to the same receptor sites as agonists and reversing receptor activity, which results in a functional antagonism of histamine. Consequently, they reduce histamine activity at the receptor sites. By doing so, these agents may inhibit histamine release and mitigate or even prevent the symptoms of urticaria[\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. Ranitidine, a histamine H2-receptor antagonist (H2RA), has been the subject of recent investigations concerning its potential toxicity and N-nitrosodimethylamine (NDMA) contamination. Current research provides relatively conclusive evidence that no significant positive correlation exists between ranitidine use and cancer incidence rates across multiple national populations. Furthermore, comparative analyses reveal no statistically significant difference in cancer risk between ranitidine users and other H2RA users [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. Recent studies have conducted systematic analyses to evaluate the potential formation of NDMA from ranitidine under simulated physiological conditions. Experimental models replicating gastrointestinal tract environments and systemic circulation parameters revealed that ranitidine exhibits negligible conversion to NDMA in both intestinal and blood compartments. This conclusion remains valid even under supplementary exposure to chloraminated tap water (containing monochloramine, NH₂Cl) at concentrations reflecting typical municipal water treatment levels. The findings suggest that physiological pH, enzymatic activity, and redox homeostasis collectively constitute effective biochemical barriers against NDMA generation from ranitidine in vivo[\u003cspan additionalcitationids=\"CR27 CR28\" citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. In certain underdeveloped regions and countries where access to omalizumab is limited, alternative treatment options for refractory CSU are required. Notably, ranitidine remains one of the recommended alternative agents in European urticaria treatment guidelines[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. The appropriate and moderate use of ranitidine may offer greater benefits than risks for certain patients with refractory CSU.\u003c/p\u003e\u003cp\u003eIn this study, we included a total of 33 patients with CU. Among these patients, total IgE levels were abnormally elevated in 11/29 (38%) cases, while Antinuclear antibodies (ANA) tested positive in 12/29 (41%) patients. Additionally, antiethyroid peroxidase antibodies (anti-TPO) antibody levels were elevated in 11/29 (38%) patients, and 24/29 (83%) exhibited insufficient levels of vitamin D. These findings are consistent with previous studies, which suggest that patients with anti-ANA and TPO-positive urticaria are more likely to exhibit resistance to conventional antihistamines[\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. Urticaria patients are more likely to develop vitamin D deficiency, which is consistent with previously reported findings [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eIn our cohort, 15 (45%) patients achieved disease control following treatment with double the standard doses of sgAHs combined with ranitidine. Based on this outcome, we categorized the participants into two groups: the response group and the nonresponse group. In the nonresponse group, 4 (22%) patients presented with annular erythematous lesions, a significantly higher proportion than that observed in the response group. This finding suggests that patients with urticaria characterized by annular or semi-annular lesions may be less responsive to treatment with ranitidine. However, research on specific types of urticaria remains limited.\u003c/p\u003e\u003cp\u003eCU can be classified into two categories based on its underlying causes: CSU and chronic induced urticaria (CIndU)[\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]. Induced urticaria includes various types, such as SD and CholU, among others [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan additionalcitationids=\"CR34\" citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e]. SD is the most prevalent form of CIndU. Many patients report experiencing chronic pruritus characterized as \"a crawling sensation\" on the skin, often without a visible rash. This discomfort can lead to scratching and the development of linear wheals. Currently, the effectiveness of available treatment options for patients with SD remains largely uncertain[\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e]. Indeed, CIndU is a common comorbidity in patients with antihistamine-refractory CSU, affecting approximately 24% of this population[\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]. In the studied population, we observed a significant reduction in the incidence of wheals in some patients after 4 weeks of treatment; however, itching persisted. In the nonresponse group, the proportion of patients with dermographism was higher than that in the response group. We concluded that ranitidine may be less effective in patients with dermographism. In contrast, the proportion of CSU patients with CholU was 20% in the response group and 0% in the nonresponse group. It has been reported that the addition of a H2RAs can be effective for patients with refractory CholU who do not respond to increased dosing of an H1RAs. However, there is limited information regarding the specific CholU subtype [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. These results suggest that ranitidine is more effective in patients with cholinergic urticaria than in those with other forms of induced urticaria.\u003c/p\u003e\u003cp\u003eAlthough the pathogenesis of CSU is not yet fully understood, it is well established that the signs and symptoms result from the activation of skin mast cells and the subsequent release of their mediators[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Recent evidence indicates that the causes of CSU include Type I autoimmunity (CSUaiTI) and Type IIb autoimmunity (CSUaiTIIb). Basic test results in CSU can help differentiate between CSUaiTI and CSUaiTIIb, with elevated CRP levels more frequently observed in CSUaiTI, while eosinophil and basophil counts are often reduced in CSUaiTIIb. Testing for IgG anti-TPO antibodies and total IgE levels are essential basic tests that should be conducted in CSU patients under specialist care to provide greater clarity regarding their condition. CSUaiTIIb is characterized by increased disease severity, the presence of concomitant autoimmune diseases, low total IgE levels, elevated IgG anti-TPO levels, basopenia, eosinopenia, poor response to antihistamines and omalizumab, and a favorable response to cyclosporine[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Currently, a high ratio of IgG anti-TPO to total IgE is considered the best surrogate marker for CSUaiTIIb[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e]. The literature also suggests that the Autologous serum skin test (ASST) may serve as a potential marker for CSUaiTIIb, alongside the direct detection of IgE and FcεRI autoantibodies. In our study, 53% of patients in the nonresponse treatment group had a positive ASST, higher than the 33% observed in the responsee treatment group. The results indicate that patients with a positive ASST are more likely to be non-responders to ranitidine treatment. Additionally, in the nonresponse group, a higher proportion of ASST-positive patients exhibited low total IgE levels, aligning with previous research findings. However, we did not observe ASST-positive patients with elevated anti-TPO antibody levels. Further validation may require studies with larger sample sizes.\u003c/p\u003e\u003cp\u003ePrevious studies have suggested that elevated D-dimer levels may indicate that urticaria patients are poor response to H1-AH therapy[\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e]. In this trial, 41% (7/17) of patients in the nonresponse group had elevated D-dimer levels, which was higher than that of the response group (33%, 4/12). Additionally, a prior study reported significantly higher rates of positive ASST results, skin scratch test outcomes, and longer disease durations in patients with high total IgE levels compared to those with low total IgE[\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e]. Nonetheless, our research did not find a statistically significant difference in these parameters (P\u0026thinsp;\u0026gt;\u0026thinsp;0.05).\u003c/p\u003e\u003cp\u003eOur clinical study demonstrated that moderate-dose ranitidine (300 mg/day) effectively controlled urticarial lesions, significantly reduced ISS7 scores (ISS7 improvement\u0026thinsp;\u0026ge;\u0026thinsp;5 points in 64% of patients), and improved quality-of-life metrics of CSU patient (achieved a DLQI score of 0 or 1 in 58% of patients). No grade 3\u0026ndash;4 adverse events were recorded during the 12-week follow-up period, indicating an acceptable safety profile. These preliminary results suggest a clinically meaningful risk-benefit ratio for this patient subgroup. Nevertheless, the single-center design, limited cohort size (n\u0026thinsp;=\u0026thinsp;33), and intermediate-term observation period necessitate larger multicenter trials with extended follow-up to establish the long-term efficacy and safety of ranitidine in refractory CSU management.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eIn CSU patients with a short disease duration, a baseline UAS7 score\u0026thinsp;\u0026lt;\u0026thinsp;25, skin lesions characterized by wind masses, no skin scratches, and a negative ASST, as well as in those with concomitant cholinergic urticaria, the addition of ranitidine may improve the disease response rate. No serious adverse reactions were observed after the addition of ranitidine, and the treatment was well tolerated. This combination can serve as an alternative treatment option for patients with refractory urticaria.\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003e\u003cstrong\u003eConflict of Interest\u003c/strong\u003e:\u003c/h2\u003e\n\u003cp\u003eThe authors declare that they have no conflict of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthical Approval:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was approved by the Research Ethics Committee of Wuhan No.1 Hospital and conformed to the Declaration of Helsinki.[2023]53.\u003c/p\u003e\n\u003ch2\u003eFunding information:\u003c/h2\u003e\n\u003cp\u003eThis work was supported by the Natural Science Foundation of HuBei Province (grant number: 2023AFB1072)\u003c/p\u003e\n\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\n\u003cp\u003eData curation and writing of the original draft: Zhou Yu, Wang Bei, Li Xinyu; Conceptualization and Methodology: Kai Chen, Jiang Ruili, Qu Zilu; Writing review and editing, supervision, and funding acquisition: Chen Liuqing, Hu Feng.\u003c/p\u003e\n\u003ch2\u003eAcknowledgements:\u003c/h2\u003e\n\u003cp\u003eWe extend our heartfelt gratitude to all the patients who participated in this study.\u003c/p\u003e\n\u003ch2\u003eData availability statement:\u003c/h2\u003e\n\u003cp\u003eThe datasets generated and analyzed during the current study are not publicly available due to privacy issues.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eKolkhir P, Gim\u0026eacute;nez-Arnau AM, Kulthanan K, Peter J, Metz M, Maurer M, Urticaria (2022) Nat Rev Dis Primers 8(1):61. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1038/s41572-022-00389-z\u003c/span\u003e\u003cspan address=\"10.1038/s41572-022-00389-z\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eAgache I, Akdis CA, Akdis M, Brockow K, Chivato T, Del Giacco S et al (2022) EAACI Biologicals Guidelines-Omalizumab for the treatment of chronic spontaneous urticaria in adults and in the paediatric population 12\u0026ndash;17 years old. 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Int J Dermatology Venereol 92(3):145\u0026ndash;149\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Antihistamines, Chronic spontaneous urticaria, Efficacy, Refractory, Ranitidine","lastPublishedDoi":"10.21203/rs.3.rs-7241257/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7241257/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSome patients with chronic spontaneous urticaria (CSU) remain inadequately controlled despite receiving double doses of H1-antihistamines (H1-AH). The high cost of omalizumab, coupled with the risk of allergic reactions in some patients, highlights the need for alternative treatment options for these refractory cases.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eObjective\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study aimed to assess the efficacy and safety of adding H1-AH plus ranitidine to the original treatment in a subset of patients with refractory urticaria.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis was a randomized, open-label study involving patients with CSU that remained uncontrolled after ≥ 2 weeks of double-dose H1-AH therapy. The primary endpoints were the Weekly Urticaria Activity Score (UAS7) response (score \u0026lt; 7) and the Urticaria Control Test (UCT) response (score ≥ 12) at week 12.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA total of 33 patients with refractory CSU were enrolled in this study. At week 12, 16 patients (48%) achieved a UAS7 response (score \u0026lt; 7), while 15 patients (45%) attained disease control (UCT ≥ 12). Overall, 21 patients (64%) showed an improvement of ≥ 5 points in the Weekly Itch Severity Score (ISS7). There were also significantly greater improvements in the Dermatology Life Quality Index (DLQI) (-2). Regarding adverse reactions, the treatment was well tolerated. A total of 4 (12%) patients experiencing AEs after the addition of ranitidine.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn refractory CSU patients with the following characteristics: short disease duration, baseline UAS7 score \u0026lt; 25, wheal-type skin lesions without excoriations, negative autologous serum skin test (ASST), or concomitant cholinergic urticaria, ranitidine add-on therapy may improve treatment response rates.\u003c/p\u003e","manuscriptTitle":"Safety and efficacy of h1-antihistamines plus ranitidine in refractory Chronic Spontaneous Urticaria","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-10-10 14:35:06","doi":"10.21203/rs.3.rs-7241257/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"2b3777a6-d747-4395-aaad-0fba02323cc2","owner":[],"postedDate":"October 10th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-02-01T23:23:55+00:00","versionOfRecord":[],"versionCreatedAt":"2025-10-10 14:35:06","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7241257","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7241257","identity":"rs-7241257","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}