Prevalence, Clinical Manifestations, Treatment, and Clinical Course of Chronic Urticaria in Elderly: A Systematic Review

Kanokvalai Kulthanan; Chuda Rujitharanawong; Kanyalak Munprom; Suphattra Trakanwittayarak; Phumithep Phumariyapong; Suthasanee Prasertsook; Patompong Ungprasert

doi:10.2147/JAA.S379912

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Review

Prevalence, Clinical Manifestations, Treatment, and Clinical Course of Chronic Urticaria in Elderly: A Systematic Review

Authors Kulthanan K , Rujitharanawong C, Munprom K, Trakanwittayarak S, Phumariyapong P , Prasertsook S , Ungprasert P

Received 4 July 2022

Accepted for publication 23 September 2022

Published 20 October 2022 Volume 2022:15 Pages 1455—1490

DOI https://doi.org/10.2147/JAA.S379912

Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 2

Editor who approved publication: Dr Luis Garcia-Marcos

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Kanokvalai Kulthanan,¹ Chuda Rujitharanawong,¹ Kanyalak Munprom,¹ Suphattra Trakanwittayarak,¹ Phumithep Phumariyapong,¹ Suthasanee Prasertsook,¹ Patompong Ungprasert²

¹Department of Dermatology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand; ²Department of Rheumatic and Immunologic Diseases, Cleveland Clinic, Cleveland, OH, USA

Correspondence: Patompong Ungprasert, Department of Rheumatic and Immunologic Diseases, Cleveland Clinic, Cleveland, OH, USA, Tel +1 216 986 4000, Fax +1 216 986 4953, Email [email protected]

Purpose: Data specific to the epidemiology, clinical features, and management of chronic urticaria (CU) in the geriatric population remain limited and not well understood. We aim to systematically review the prevalence, clinical manifestations, treatment, and clinical course of elderly patients with CU.
Patients and methods: Original articles that included data of elderly (aged > 60 years) with CU that were published until February 2021 were searched in PubMed, Scopus, and Embase using predfefined search terms. Related articles were evaluated according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses recommendations.
Results: Among the included 85 studies and 1,112,066 elderly CU patients, most (57.4%) were women. The prevalence of elderly CU in the general population ranged from 0.2– 2.8%, and from 0.7– 33.3% among all CU patients. Compared to adult CU, elderly CU patients had a higher percentage of wheal alone (73.9%), and lower rate of positive autologous serum skin test and atopy. Gastrointestinal diseases were the most common comorbidity (71.9%), and there was a high rate of malignancies and autoimmune diseases. Second generation H₁-antihistamines were commonly used, and achievement of complete control was most often reported. Omalizumab was prescribed in 59 refractory patients, and a significant response to treatment was reported in most patients. The treatment of comorbidities also yielded significant improvement in CU.
Conclusion: Elderly CU was found to be different from adult CU in both clinical and laboratory aspects. H₁- antihistamines are effective as first-line therapy with minimal side-effects at licensed doses. Treatment of secondary causes is important since the elderly usually have age-related comorbidities.

Keywords: prevalence, clinical manifestations, treatment, chronic urticaria, elderly, systematic review

Introduction

People are now living longer due to new innovations in both technology and modern medicine.¹ The result has been a doubling of global life expectancy over the past century, and an increase in the aging population worldwide.² The World Health Organization and the United Nations define elderly as age ≥60 years and age ≥65 years, respectively.^3,4 Thus, elderly-specific medical care has become and will continue to be a top priority of global public health.

Chronic urticaria (CU) is one of the most common pruritic conditions in the older population.^5,6 CU is characterized by the presence of recurrent wheal, with or without angioedema, occurring at least twice a week for longer than 6 weeks.⁷ CU can be classified into two subtypes: chronic spontaneous urticaria (CSU) and chronic inducible urticaria (CIndU).⁷ The pathogenesis of CU is still unclear, but it is thought to be related to histamine, other mediators, and cytokines that are released from activated mast cells by degranulation.^7–9 Among all patient with CU, 4.1–5.5% are elderly.¹⁰⁻¹² Moreover, several systemic and autoimmune diseases have been reported to be associated with CU in the elderly population, including hypertension, chronic kidney disease, diabetes mellitus, thyroid disease, atopic dermatitis and other allergic diseases, cardiac and cerebral vascular disease, and cancer.^11,13–20 CU can also affect various aspects of patient quality of personal and social life, including sleep disorders, anxiety and depression, sexual dysfunction, and decreased work performance.^21–23

Our current understanding of CU in the elderly is still limited since the number of studies describing the clinical manifestations and responses to treatment of CU in the geriatric population with CU remains comparatively small. The International EAACI/GA² LEN/EuroGuiDerm/APAAACI Guideline for the Definition, Classification, Diagnosis and Management of Urticaria recommends second generation H₁-antihistamine (sgAH₁) as the first-line treatment for CU.⁷ If disease control is inadequate after 2–4 weeks of treatment, increasing the dose up to 4-fold of the standard dose of sgAH₁s is recommended. For antihistamine-refractory patients, omalizumab and cyclosporine (CsA) are the treatments of choice.⁷ However, the use of some antihistamines and other medications to treat older patients with CU can be limited due to several factors. In recalcitrant cases, other differential diagnoses related to underlying medical conditions should be considered. In an effort to bridge this knowledge gap, this systematic review was conducted to investigate the reported epidemiology, clinical features, treatments, and clinical course in elderly CU from all available studies.

Methods

Protocol and Registration

The protocol of this systematic review has been reviewed and approved by the Siriraj Institutional Review Board (SIRB), Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand with SIRB Protocol No. 107/2564 (Exempt), and followed the standard protocol of Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA).²⁴ Studies published until February 2021 were searched in the PubMed, Scopus, and Embase databases. The search terms were “urticaria and elderly”, “urticaria and aging”, and “urticaria and geriatric”.

Eligibility Criteria for Systematic Review

Case reports, case series, randomized controlled trials (RCTs), prospective cohort, retrospective cohort, and other types of studies that reported the epidemiology and clinical manifestation of CU in patients aged equal to or greater than 60 years were included. Due to the relatively limited number of studies of CU in the elderly, we included the studies performed in patients aged equal to or greater than 60 years, case reports and case series, aiming to collect data from available published evidence as much as possible. Treatment data was also extracted, but it was not part of the inclusion criteria (ie, studies that described only epidemiology and clinical manifestation without a description of treatment were eligible). Five investigators (KK, CR, KM, ST, and SP) independently screened all titles and abstracts of all retrieved articles. Potentially eligible articles were reviewed in full-text to determine their final eligibility. That process was also independently conducted by the same five reviewers. Any disagreement was resolved by discussion and consensus among the five reviewers.

Data Extraction

The following data were independently extracted by the same five investigators (KK, CR, KM, ST, and SP): 1) first author’s name and the year of publication; 2) number of reported patients; 3) epidemiology; 4) clinical manifestations; 5) laboratory investigations; and 6) treatment and clinical course. Response to treatment was classified into four groups, as follows: i) complete control was defined as free of symptoms on continuation of treatment; ii) marked improvement was defined as symptoms having improved considerably, but that some symptoms were still present during treatment; iii) partial improvement was defined as partial reduction of severity of symptoms during treatment; and iv) no improvement was defined as no improvement of symptoms while on medications.

Statistical Analysis

Descriptive statistics, including mean plus/minus standard deviation and number and percentage, were used to describe demographic data, clinical manifestation, prevalence, laboratory findings, treatment, and clinical course. All data were analyzed using PASW Statistics for Windows (version 18.0; SPSS, Inc., Chicago, IL).

Results

From the three databases that were searched, 17,645 articles were identified (6,079 from PubMed, 5,579 from Scopus, and 5,987 from Embase). Of those, 3,369 duplicate articles were excluded. The remaining 14,276 articles underwent title and abstract review. This process eliminated 14,127 articles that did not meet the inclusion criteria. The remaining 149 articles underwent full-text review. Of those, 85 articles (three randomized controlled trials, 12 prospective cohort studies, 34 retrospective cohort studies, one case control study, 16 cross-sectional studies, eight cases series, and 11 case reports) fulfilled the inclusion criteria and were included for systematic review (Figure 1).

Figure 1 Flow diagram of the literature review process in this systematic review. Eighty-five articles were suitable for the inclusion criteria and were included in our systemic review. There were three randomized controlled trials, 12 prospective cohorts, 34 retrospective cohorts, one case-control, 16 cross-sectional, eight case series, and 11 case reports.

Proportion of the Elderly Among All Patients with CU, and the Prevalence of CU Among the Elderly

As shown in Table 1, the percentage of elderly among all CU patients from a single-center cohort ranged from 0.7% to 18.0%,^{10,12,20,25–28} while the reported percentage in general population ranged from 14.1% to 33.3%.^19,29–34 Only two studies reported the percentage of elderly among all CSU patients in the general population (15.6% and 31.5%),^34,35 while the percentage of elderly among CSU patients from single-center studies ranged from 6.7% to 21.7%.^20,36–42 The percentage of elderly CIndU patients was reported in five studies.^{32,34,43–45} The highest proportion was described in a general population study (16.3%).³² The prevalence of elderly CU in the general population was reported to range from 0.2% to 2.8%^29,33,35,46 (Table 2).

Table 1 The Reported Prevalence of Chronic Urticaria, Chronic Spontaneous Urticaria, and Chronic Inducible Urticaria in Elderly Patients Relative to All Reported Cases of These Disorders

Table 2 The Reported Prevalence of Chronic Urticaria in the Elderly Population

Epidemiological Data

Clinical features and demographic data of the elderly with CU are summarized in Table 3. Women accounted for 57.4%, 63.9%, and 57.9% of elderly CU, CSU, and CIndU, respectively. The mean age at presentation among all CU patients was 70.4±6.2 years. Most presented with wheal alone (73.9%), followed by wheal with angioedema (25.9%). Only 0.2% presented with wheal and anaphylaxis. The average duration of disease prior to diagnosis was 1.9±3.6 years. Allergic rhinitis, asthma, and allergic dermatitis were the three most common associated atopic diseases. Cold urticaria, symptomatic dermographism, and cholinergic urticaria were found in 10.9%, 7.3%, and 3.5% of elderly CU patients, respectively.

Table 3 The Reported Demographic and Clinical Characteristics of Elderly Patients with Chronic Urticaria (CU), and Compared Between the Two Subtypes of CU – Chronic Spontaneous Urticaria and Chronic Inducible Urticaria

Severity of CU was reported in 19 studies, mostly moderate-to-severe disease activity.^{11,20,40,47–62} Urticaria activity score (weekly total score 42) was used in 13 studies, and the average score among all studies was 22.1±12.2.^{20,40,48,53–55,57–63} The other scores used to report severity were Visual Analog Scale (VAS; total score 10),⁵⁴ Urticaria Activity Score (UAS; total score 9),⁵⁰ Urticaria Activity Score (UAS; total score 15),¹¹ Urticaria Severity Score (USS; total score 93),⁵¹ and Treatment Score (TS; total score 5).^49,53 Twelve CSU studies reported severity using Urticaria Activity Score (UAS; weekly total score 42) with an average score among studies of 26.1±12.2.^{40,53–55,57–60,62} Severity of CIndU was reported in heat urticaria, which showed a temperature threshold of 38°C, and in cold urticaria which showed 22 mm for the wheal and 40 mm for the flare by cold stimulation test.^52,56

Elderly CU Patients Suffer from Various Age-Related Comorbidities

The reported comorbidities of study patients are shown in Table 3. Unspecified gastrointestinal (GI) disease was the most commonly reported comorbidity among elderly CU patients (71.9%), with the majority of cases collected from a large national database (Korean Health Insurance Review and Assessment Service: HIRA).⁶⁴ The reported prevalence of coronary and cerebral vascular disease were also high at 36.7%. The prevalence of dyslipidemia, hypertension, obesity, and diabetes mellitus in elderly CU patients was 42.9%, 18.6%, 16.7%, and 12.6%, respectively. Thyroid diseases were reported in 20 studies,^{10,20,37,45,49–51,53,61,62,65–74} and some of them were related to autoimmune disorders. For example, Grave’s disease and Hashimoto’s disease was reported in 44.4% and 20.8% of aging CU, respectively. Other common comorbidities were osteoporosis (42.9%), Raynaud phenomena (33.3%), gout (20.0%), avascular hip necrosis (20.0%), systemic lupus erythematosus (20.0%), and anemia (20.0%). Malignancies were also reported at a high rate. Most malignancies were unspecified but, among those that were specified, GI cancer was the most prevalent (60.0%). Other possible causes or aggravating factors of CU were paronychia (100.0%), stress (27.3%), unspecified drug allergy (9.1%), parasitic infection (4.7%), collagen vascular disease (3.2%), unspecified food allergy (3.0%), insect bite (2.4%), and aspirin intolerance (2.0%).

Laboratory results in Elderly with CU

As shown in Table 3, a positive autologous serum skin test (ASST) was found in 47.5% of elderly CU patients, which was less than in elderly CSU patients (54.9%). A Basophil histamine release test was reported in six studies,^{50,61,75–78} and the result was positive in five of 13 tested patients (38.5%). There were 22 studies that reported the level of total serum IgE, and 16 of those studies reported the IgE value. The average level among those 16 studies was higher than the normal upper limit.^{11,20,37,40,49,50,52,55,57,61,62,76,79–82} The other six studies reported only whether the level was elevated or not. The value was elevated in 42.1% of patients,^{58,69,75,83–85} and this rate was similar to the 43.8% rate reported in elderly CSU. Erythrocyte sedimentation rate (ESR) was increased in 26.8% and 25.4% of elderly CU and CSU, respectively. Positive D-dimer was found in 50.0% of elderly CU patients, and elevated prothrombin fragment was found in 75.0%.⁸⁶ Antinuclear antibody (ANA) was reported in 13 studies^{10,45,51,56,58,63,65,69,79,82,83,85,87} with an average positivity rate of 16.0% among those studies. Anti-FcεRI antibody was reported in one study (66.7% positive).⁷² Abnormal thyroid hormone was common since it was reported in five of 21 studies.^{65,71–73,77} No study reported abnormal free T3, but 13.0% of elderly CU patients had abnormal free T4 hormone, and 18.2% had abnormal thyroid stimulating hormone. Twenty-four studies reported thyroid autoantibodies with a positivity rate of antithyroid peroxidase antibodies of 26.4%, and a positivity rate of antithyroglobulin antibodies of 15.6%.^{10,11,40,50,51,55,56,60,63,65–67,69–73,77,78,82,83,85,88,89}

Treatments for CU

Among the elderly who achieved complete control with the use of AH₁, sgAH₁ was most often used at a regular dose (24 of 34 patients), whereas first generation H₁-antihistamine (fgAH₁) was prescribed at a high dose (2 of 2 patients). Side-effects of antihistamines were reported in one study. A combination of multiple high-dose fgAH₁, which were hydroxyzine (dose: 25–200 mg/day), diphenhydramine (dose: 25–200 mg/day), and doxepin (dose: 25–125 mg/day), showed no additional benefit and caused severe sedation. Treatment in those cases was later changed to omalizumab.⁶⁰ Omalizumab was prescribed in 15 studies. Complete control was observed in 59 of 89 patients, and the prescribed dose ranged from 150 to 300 mg every 2–4 weeks. Fifty patients from five studies received omalizumab alone.^{48,76,81,90,91} Others received omalizumab in combination with other treatments, including with H₁-antihistamine (AH₁) in seven patients from five studies,^{49,50,57,58,61} and systemic corticosteroid in two patients from one study.^55,60 Side-effects of omalizumab were reported in three studies.^62,81,90 Two patients experienced nausea, two patients reported asthenia that spontaneously resolved within 48 hours, and one patient had pain at the injection site.

Treatment of Secondary Causes Should Be Considered a Strategy for Controlling CU

Treatment of secondary causes was also effective for controlling CU in the elderly. Thirty-nine studies described the treatment of secondary causes and the outcomes of treatment (Figure 2 and Table 4). More specifically, the following treatments, prescriptions, or procedures improved CU symptoms in the elderly: treatment for Helicobacter pylori (H. pylori) infection,⁶³ treatment for Strongyloides infection,⁹² treatment for thyroid diseases,^73,88 prescription of immunosuppressants for malignancies,^79,83,93 prescription of intravenous immunoglobulin (IVIG)^53,54,60 or sulfasalazine to treat recalcitrant CSU,⁹⁴ and surgical removal of adenoma/neoplasms.^{69,84,85,89,95–97}

Table 4 The Reported Treatment for and Clinical Course of Chronic Urticaria in the Elderly

Figure 2 Treatments and responses to treatment among elderly with chronic urticaria.

Abbreviations: AH₁,H_1-antihistamine; fgAH₁, first generation H₁-antihistamine; IVIG, intravenous immunoglobulin; LTRA, leukotriene receptor antagonist; MTX, methotrexate; NA, not available/not applicable; sgAH₁, second generation H₁-antihistamine.

Notes: Some patients received more than one type of treatment.

Follow-Up Time, Tapering, Relapse, and Mean Duration of Treatment

The follow-up time after completion of treatment was mentioned in 16 studies,^{51,53,54,58,62,69,73,82–85,88,89,92,94,95} and the average follow-up time was 17.5 months. Some patients who had already achieved complete control continued their previous medication during the follow-up period, such as sulfasalazine and sgAH₁, until they could be tapered off.⁹⁴ Methotrexate (MTX) was tapered off in two patients, but one of them relapsed.⁸³ Four patients continued to receive omalizumab maintenance at the same dose with an attempt to increase the interval between doses.^55,60,91 One patient was prescribed fgAH₁ as needed, but there was no report of the actual frequency of use.⁸⁸ Another patient continued levothyroxine for 2 years before tapering, but relapse occurred. The dose was increased back to the initial dose and complete control was re-established.⁵¹ The average duration of treatment in this study was 205.8 days (6.9 months).

Discussion

The results of this systematic review revealed some similarities and differences between adult CU and elderly CU. Previously reported prevalence of CU in adult population ranges from 0.1% to 3.4%, which is relatively similar to the 0.2% to 2.8% prevalence of CU in the elderly.^33,98 Our review also showed variation between prevalence in various geographic areas. As shown in Table 1, large population and nationwide studies showed a relatively higher prevalence of elderly in the CU population than smaller studies. However, larger studies and smaller studies reported a similar prevalence of CU in the overall elderly population (Table 2).

Even if women formed the majority of this study, which was similar to previous elderly and adult CU reports,^{10,11,23,99,100} some clinical presentations of elderly patients differed from adult CU. Comparison of the reported demographic and clinical characteristics of elderly patients with CU and those of non-elderly is shown in Table 5. Although the majority of both groups presented with wheal alone, its proportions in the elderly were higher than in adults, ranging from 33% to 87% across the studies, while the prevalence of concurrent angioedema was less.^{9,10,12,20,37,40,90} Wheal with anaphylaxis in our review was found only in one case report of the elderly with cold urticaria, which was the type that could have concurrent anaphylaxis up to 3.7–38.0%.^44,101–107 CSU was the most common subtype among the elderly, similar to adult CU.^{10,20,26,45,108–111} Concerning CIndU, symptomatic dermographism (SD) was reported as the most common CIndU in both groups.^{10,20,45,74,108,112} Similar to the report of Ban et al,¹¹ history of atopy, which is known to be associated with CU, was found at a relatively lower rate in this study than adult CU,^{10,11,20,37,45,64,74,90} in contrast with some previous studies.^10,11,18 Regarding comorbidities, Lapi et al³⁵ reported the risk of developing CU to be related to numerous factors. Gastrointestinal diseases, being the most common concomitant disease, together with coronary heart diseases, cerebrovascular diseases, metabolic syndrome, autoimmune diseases, thyroid diseases, psychological problems, and malignancies, were all reported at high rates in elderly CU. These findings were consistent with previous studies that reported CU to be associated with increased risk of having metabolic syndrome in both adults and the elderly.^20,113–115 Moreover, the risk of developing metabolic syndrome was also found to increase with age.^116,117 As reported by Zbiciak-Nylec et al¹¹⁸ that later onset of urticaria symptoms can result from obesity. Similar to previous studies, autoimmune diseases including autoimmune thyroid diseases, rheumatoid arthritis, and systemic lupus erythematosus had been reported in high rates in all age groups of CU patients, but much more in the elderly.^{17,70,90,119–123} This can be a result from increasing production of autoantibodies with aging, as Ramos-Casals et al¹²⁴ proposed. In addition, a previous nationwide study reported depression to be common in adult CU, while elderly CU was reported mainly in dementia and other non-specific psychological problems.¹⁰⁰

Table 5 Comparison of the Reported Demographic and Clinical Characteristics of Elderly Patients with Chronic Urticaria (CU) with Those of Non-Elderly

Table 6 Quality and Risk of Bias Assessment of Included Articles in Systematic Review

The high rate of malignancies, both hematologic and non-hematologic, in the present study may be explained by the advanced age. Most studies reported CU patients to be at high risk of developing cancers, and the incidence of cancer also increased with age.^{19,89,125,126} A possible mechanism is alteration of the immune system by the tumor.¹²⁶ Age-appropriate malignancy screening is, therefore, strongly encouraged for early detection and treatment, which will improve the outcomes of both cancer and urticaria.^89,93,97,126

The high prevalence of thyroid autoantibodies in both geriatric and adult CU suggests the relationship between CU and thyroid autoimmunity,^{10,11,40,67,70,120,123,127} even though this study and the previous report showed no difference of thyroid autoantibodies between the two groups.¹¹ Focusing on infections, hepatitis B virus was the only infection in this study that was reported at higher prevalence (12.7%) than in previously reported general CU patients (0–3.6%).^128,129 There was no difference in other laboratory findings, such as ESR, ANA, and total serum IgE levels. However, elderly CSU was reported to have a relatively lower proportion of positive ASST than adult CSU, as in the study by Magen et al.²⁰

Treatment of CU in elderly patients usually follows the same guidelines as the general population. SgAH₁ is recommended as the first-line treatment for elderly CU. The regular dose of SgAH₁ is generally sufficient to achieve complete control in most patients, with a higher proportion of response in elderly CU than adults. This was in line with the finding of a lower rate of ASST in the elderly. As ASST positivity correlates with higher severity and longer duration of disease of CSU,^{127,130–132} geriatric patients may have less severe CU symptoms than adult CU, resulting in fewer associated angioedema and good response to standard treatment. Updosing to a higher dose or 4-times was also reported the good efficacy in SgAH₁. For patients who fail on antihistamines, successful symptom control has been achieved by the use of omalizumab 150–300 mg every 2–4 weeks.

Some patients with autoimmune thyroiditis and hypothyroid were treated by levothyroxine, which also helps in improving urticaria.^51,67,73 The risks and benefits of these third-line drugs have not been sufficiently explored and additional studies are needed.^7,83 Another treatment strategy that significantly improved CU symptoms was treatment of secondary causes concurrent with standard treatments, especially in aging patients in whom autoimmune disorders, malignancies and infections are more common. A systematic review by Kolkhir et al¹³³ found CSU to be quite common in patients with strongyloidiasis. Its pathogenesis may be due to eosinophil and complement activation leading to skin mast cell activation. Magen et al⁶³ and Zubrinich et al⁹² reported an association between H. Pylori infection, Strongyloides infection, and CU. Treatment with standard antiparasitic drugs yielded complete control.^63,92,133 Therefore, treatment of these associated comorbidities, including infection, might result in a better CU control.

Limitations

Most of the included articles were retrospective studies, case reports, and case series, which are inherently classified as having a lower level of evidence (Table 6). Only three randomized controlled trials were eligible to be included in the analysis, hence, the number of control groups was low. Furthermore, only a few studies had a study population consisting only of elderly patients. These limitations further underscore the potential value of this study and make clinicians more aware that more prospective studies are needed on cases of CU in the elderly.

Conclusions

This systematic review found that the prevalence CU ranges between 0.2–2.8% in the elderly population. CSU was still the most common type, and exhibited a female predominance. Compared with adult CU, a lower rate of atopy, more age-related comorbidities including metabolic syndrome, autoimmune disorders, and malignancies, a lower rate of associated angioedema, and lower ASST positivity, were reported in elderly CU. The use of antihistamines often yielded good results as first-line treatment. Omalizumab was effective in AH₁-resistant cases, and other differential diagnosis should be considered in patients refractory to standard treatment. More prospective studies are necessary to further elucidate the characteristics of the disease in this age group.

Abbreviations

AH₁, H₁-antihistamine; CIndU, Chronic inducible urticaria; CSU, Chronic spontaneous urticaria; CsA, Cyclosporine; CU, Chronic urticaria; ESR, Erythrocyte sedimentation rate; fgAH₁, First generation H₁-antihistamine; GI, Gastrointestinal; H. pylori, Helicobacter pylori; IVIG, Intravenous immunoglobulin; MTX, Methotrexate; RCT, Randomized controlled trial; SD, Symptomatic dermographism; sgAH₁, Second generation H₁-antihistamine.

Acknowledgment

The authors gratefully acknowledge Saowalak Hunnangkul, PhD for her assistance with statistical analysis, and for her advice regarding the systematic review process.

Disclosure

This research did not receive any specific grants from funding agencies in the public, commercial, or not-for-profit sectors for the present study. All of the authors report no conflicts of interest in this work.

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