Dermatology: Practical and Conceptual Original Article | Dermatol Pract Concept. 2022;12(4):e2022148 1 Omalizumab for the Treatment of Chronic Spontaneous Urticaria: Association Between Body Mass Index and Outcome Irene Russo1,2, Sara Cazzolla1, Francesca Pampaloni1, Mauro Alaibac1 1 Unit of Dermatology, Department of Medicine (DIMED), University of Padova, Padua, Italy 2 Soft-Tissue, Peritoneum and Melanoma Surgical Oncology Unit, Veneto Institute of Oncology (IOV)- IRCCS, Padua, Italy Key words: omalizumab, chronic spontaneous urticaria, BMI Citation: Russo I, Cazzolla S, Pampaloni F, Alaibac M. Omalizumab for the treatment of chronic spontaneous urticaria: association between body mass index and outcome. Dermatol Pract Concept. 2022;12(4):e2022148. DOI: https://doi.org/10.5826/dpc.1204a148 Accepted: January 21, 2022; Published: October 2022 Copyright: ©2022 Russo et al. This is an open-access article distributed under the terms of the Creative Commons Attribution- NonCommercial License (BY-NC-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. Funding: None. Competing interests: None. Authorship: All authors have contributed significantly to this publication. Corresponding author: Francesca Pampaloni, Unit of Dermatology, Department of Medicine (DIMED), University of Padova, via Gallucci 4, 35128 Padua, Italy. Phone 00390498212901 E-mail: francesca.pampaloni@gmail.com Introduction: Omalizumab has been recently registered as a third-line therapy for chronic sponta- neous urticaria. Objectives: In this study, we aimed to provide real life data by reporting our experience with omali- zumab in the treatment of chronic spontaneous urticaria. Methods: A retrospective data analysis was conducted on 40 patients affected by chronic spontaneous urticaria and treated with omalizumab at the Dermatology Unit of Padova University Hospital. Demo- graphic, anthropometric, and clinical data have been collected. Results: Overall, the majority of patients (23 patients, 57.5%) achieved complete recovery by taking omalizumab and 17.5% (7 patients) had a partial response. The majority of patients who did not have a response to omalizumab had a body mass index (BMI) > 25 kg/m2. Conclusions: Our study suggests that omalizumab is a safe and effective treatment for chronic spon- taneous urticaria. We identified BMI as a critical biological factor that significantly impacts the out- comes of omalizumab treatment. Our findings also suggest a potential use of BMI as a predictive biomarker for omalizumab treatment. An up-dosing of omalizumab may be proposed in patients with high BMI to achieve a better control of the disease. ABSTRACT 2 Original Article | Dermatol Pract Concept. 2022;12(4):e2022148 Introduction Chronic spontaneous urticaria (CSU) is a common disease, however, epidemiological data currently available on CSU prevalence ranging from 0.02% to 1% in different studies [1,2]. It is clinically characterized by the recurrent appear- ance of itch, wheals and/or angioedema for more than 6 weeks in absence of a known trigger [3]. It is often a self- limiting disease lasting no more than 2-5 years; however in 20% of patients lasts for more than 5 years. Many factors may play a role in the pathogenesis of chronic idiopathic urticaria, including infections, diet, drugs, emotional fac- tors, and stress [1,4]. Chronic spontaneous urticaria highly impacts quality of life of patients affected. Pruritus causes variable discomfort, as well as cutaneous wheals which may harm individual physical appearance and social life. The first line therapy for CSU consists in the use of non-sedating H1-antihistamines. If the response is inadequate after two weeks of treatment, increasing the antihistamine dosage up to four-fold is recommended as second-line therapy [2,4]. Omalizumab, a humanized anti-IgE monoclonal antibody, that was primarily approved for the treatment of moderate/ severe asthma has been recently registered for CSU treatment as a third-line therapy [5-8]. Objectives In this study, we aimed to provide real life data by reporting our experience with omalizumab in the treatment of CSU. Methods A retrospective data analysis was conducted on 40 patients affected by CSU and treated with omalizumab between 2016 and 2019 at the Dermatology Unit of Padova University Hospital. All patients provided written informed consent. The pa- tients included were aged over than 18 years with at least 6 months history of chronic idiopathic urticaria. The severity of the urticaria was assessed thanks to the Urticaria Activity Score (UAS) and established both daily and weekly (UAS7), based on the presence of wheals and itching. All patients received a 300 mg subcutaneous injection of omalizumab every 4 weeks for at least 6 months. Once a month, follow-up visits were scheduled together with the omalizumab infusions. The following data were collected: birth date, sex, height, weight, date of urticaria diagnosis, severity of the disease, previous urticaria therapies, co- morbidities, and concomitant medications. The body mass index (BMI) value was calculated (in kg/m2) to classify pa- tients as underweight (BMI < 18.4 kg/m2), normal weight (18.5 kg/m2≤ BMI ≤ 24.9 kg/m2), overweight (25 kg/m2≤ BMI ≤ 29.9 kg/m2) and obese (BMI ≥ 30 kg/m2). The date of the first omalizumab administration, the number of therapy cycles and the date of the last infusion were recorded as well as any adverse events during or after omalizumab admin- istration. The outcome of the treatment with omalizumab was evaluated based on the patient’s report, any objective improvement or worsening, and reduction of UAS7. UAS7=0 was considered as complete response, while a 90% reduc- tion in UAS7 was considered as a partial response. Benefit achieved after a single course of omalizumab was considered a partial response. Results The study included 40 patients with the following demo- graphic characteristics: 30 females (75%) and 10 males (25%), with a mean age of 49 years (range: 21- 81 years). The minimum BMI detected was 17.8 kg/m2, while the max- imum was 34 kg/m2, with an average value of 24.1 kg/m2. The patients were divided in underweight, normal weight, overweight and obese (Table 1). The date of urticaria diag- nosis was between 1994 and 2019. The mean age of patients at the time of the diagnosis was 45 years. All patients were affected by severe disease with UAS > 4 and UAS7 > 30 before starting treatment with omalizumab. Medications used before omalizumab for the treatment of CSU included three main classes of drugs: antihistamines (85% of patients, mainly desloratadine), glucocorticoids (62.5% of patients, mostly prednisone) and immunosuppressants (27.5% of patients, primarily cyclosporine). Furthermore, 27.5% of patients followed a histamine-free diet, 10% of cases received a supplementation with nicotinamide, while 5% of patients were treated with UVB phototherapy. The majority of patients (80%) presented comorbidities includ- ing allergic rhinitis (20%), hypothyroidism (20%), nickel al- lergy (15%), grasses allergy (12.5%) and atopic dermatitis Table 1. Classification of patients based on the BMI value according to the WHO: underweight (<18.5 kg/m2), normal weight (18.5- 24.9 kg/m2), overweight (25- 29.9 kg/m2) and obese (>30 kg/m2) Patient Underweight Normal Weight Overweight Obese Female, N (%) 2 (5%) 17 (42,5%) 7 (17,5%) 4 (10%) Male, N (%) 0 6 (15%) 4 (10%) 0 Original Article | Dermatol Pract Concept. 2022;12(4):e2022148 3 (12.5%) were detected. Simultaneously to the omalizumab therapy, many patients have taken various therapies for both CSU and their concurrent diseases including antihistamines (60%), glucocorticoids (55%), levothyroxine (15%). In ad- dition, 15% of patients continued to follow a histamine-free diet and 12.5% were taking nicotinamide. Overall, 30 patients (75%) completed the entire course of omalizumab therapy, while 10 of them (25%) discontin- ued omalizumab due to acute side effects (discontinuation at the first dose, in 2 patients), other diseases (2 patients) or ineffectiveness (6 patients). Based on the results obtained, patients were classified into three categories: no response (10 cases, 25%), partial response (7 patients, 17.5%), complete response (23 patients, 57.5%) (Figure 1). The majority of patients who did not have a response to omalizumab had a BMI > 25 kg/m2. Binomial logistic regression enables us to determine which of our independent variables have statistically signif- icant effect on outcome; considering age, sex and BMI as variables, emerged that BMI has a statistically significant effect (P = 0.042), and odds ratio < 1 indicates a positive predictive value of better response to therapy (Table 2). Conclusions In our cohort patients were predominantly female (M:F ratio was 1:3), according to the literature, which reports a prev- alence of CSU two times higher among women than man. It may be explained by the role of autoimmunity in CSU 60% 50% 40% 30% 20% 10% 0% NO RESPONSE 25% 17.5% 57.5% NO RESPONSE PARTIAL RESPONSE OUTCOME TO OMALIZUMAB TREATMENT PARTIAL RESPONSE COMPLETE RESPONSE COMPLETE RESPONSE Figure 1. Outcome of omalizumab treatment. Complete response: UAS7=0; Partial response: 90% reduction of UAS7 values; 25% of patients (10 patients) had no response; 17.5% of patients (7 patients) reported partial response, while 57.5% (23 patients) had a complete response to omalizumab. Table 2. Model coefficients – outcome Predictor Estimatea SE Z P Odds ratio Intercept 3.8904 2.5292 1.538 0.124 48.930 BMI -0.2105 0.1037 -2.029 0.042 0.810 Age 0.0458 0.0315 1.452 0.147 1.047 Sex: M – F 0.8918 1.0390 0.858 0.391 2.439 BMI = body mass index; F =female; M = male; SE = standard error. aEstimates represent the log odds of “Outcome = yes” versus “Outcome = no” 4 Original Article | Dermatol Pract Concept. 2022;12(4):e2022148 for patients affected by asthma the recommended dose of omalizumab changes according to the body weight of the patient, a fixed dose regimen is recommended for CSU re- gardless of the body weight and total IgE levels. In the re- cent years, there have been several studies on updosing of the drug, suggesting that the individualized approach for urticaria treatment with omalizumab is useful [16]. Patients with a higher BMI have been found to require higher doses to control the disease [17]. A step-wise approach starting from 450 mg and then updosing to 600 mg has been pro- posed if there is no response after 3 months of treatment in CSU patients [17]. Furthermore intervention on lifestyle through a combination of dietary changing and physical ac- tivity should be recommended in patients with high BMI. Total IgE serum level do not justify an omalizumab dose changing however, it is a reliable biomarker predicting re- sponse to omalizumab in CSU since levels are significantly higher in responder than non-responder patients [18]. The main limitation of our study is the small number of patients included. Furthermore, all patients had a high UAS and some patients continued antihistamines and corticoste- roids during omalizumab. We know that these may be con- founding factors that may have influenced the outcome. In conclusion, in this study we identified BMI as a critical biological factor that significantly impacts the outcomes of omalizumab treatment. Our findings also suggest a poten- tial use of BMI as a predictive biomarker for omalizumab treatment. An up-dosing of omalizumab may be proposed in patients with high BMI to achieve a better control of the disease. References 1. Maurer M, Weller K, Gime A, et al. Unmet clinical needs in chronic spontaneous urticaria. A GA²LEN task force report. Allergy. 2011;66(3):317-330. DOI: 10.1111/j.1398-9995.2010.02496.x. PMID: 21083565. 2. Nettis E, Foti C, Ambrifi M, et al. Urticaria: recommendations from the Italian Society of Allergology, Asthma and Clinical Im- munology and the Italian Society of Allergological, Occupational and Environmental Dermatology. Clin Mol Allergy. 2020;18:8. DOI: 10.1186/s12948-020-00123-8. PMID: 32390768;PMCID: PMC7201804. 3. Zuberbier T, Abdul Latiff AH, Abuzakouk M, et al. The inter- national EAACI/GA²LEN/EuroGuiDerm/APAAACI guideline for the definition, classification, diagnosis, and management of urticaria. Allergy. 2022;77(3):734-766. DOI: 10.1111/all.15090. 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