Exploring the Disease Duration of Urticaria and Associated Determinants in Primary Care

Abstract

Most patients presenting with new-onset urticaria are expected to have short-lived symptoms, acute urticaria (AU). Initial treatment of urticaria is therefore generally limited to a wait-and-see approach and second-generation (low dose) H1-anthistamines [1]. However, it is estimated that 0%–39% of patients develop chronic urticaria (CU), mainly based on outdated studies that focused on children with a follow-up time of up to 2 years [2]. Determining the exact proportion of CU patients is essential, because a substantial part of this population requires long-term additional treatment in the second and third line due to high severity. Identifying early indicators of CU could further improve treatment optimization, timely referral and adequate expectation management. We aimed to investigate disease duration patterns of urticaria and potential determinants of CU in a large unselected primary care population using data from the ‘Julius General Practitioner Network’ (JGPN) database in the Netherlands, where all patients with new-onset urticaria first present to a general practitioner (GP). The JGPN database (≈450,000 patients) is representative of the Dutch population and contains information on all GP consultations, including diagnoses coded using the International Classification of Primary Care (ICPC) system with corresponding contact dates [3]. A retrospective cohort of all patients with an initial GP consultation for urticaria (ICPC S89) between January 1st 2010 and December 31st 2019 (data lock) was included (N = 18,284). As specific ICPC codes distinguishing AU from CU are lacking, AU was considered when the time between the first and last consultation was ≤ 6 weeks and CU when consultations were > 6 weeks apart. To reduce misclassification, patients with only two urticaria-related GP contacts > 6 months apart were excluded (N = 1392; 7%), as it was unclear whether these cases represented two separate AU episodes or ongoing CU. Disease duration was estimated from the time between the first and last consultation. Informed consent was not required and the study was approved by the Ethical Committee Utrecht, The Netherlands (21/420). A total of 16,892 urticaria patients (mean age 30 ± 22; 62% female) initially presented between 2010 and 2020. Most patients (75%, n = 12,588) had urticaria lasting < 1 week, consistent with previous older studies [2]. The proportion of patients with disease duration ≤ 6 weeks was 83% (n = 14,056), fulfilling AU criteria. Subsequently, 17% (n = 2836) were considered CU, with a median disease duration of 1 [0–2] year and a median number of 4 [3-6] urticaria-related GP consultations. Only one population-based study using insurance data investigated the proportion developing CU among both children and adults with new-onset urticaria (n = 49,129), reporting a far lower rate of 6% [4]. However, patient selection differed significantly, as only urticaria patients with at least two visits and a prescription were included, likely excluding many AU and mild CU patients who did not need or obtain medication over the counter. To identify early indicators of CU, multivariable logistic regression analyses were performed using clinical characteristics present before or at initial urticaria-related contact that were deemed relevant. Sensitivity analyses were performed for multiple thresholds of disease duration (defined as having a duration of at least 1 week, 4 weeks, 1 year, 5 years). In the primary analysis, higher age at urticaria onset (log-transformed OR 1.15, 95% CI 1.10–1.19), BMI ≥ 25 (OR 1.37, 95% CI 1.20–1.56), and prednisolone use within the first week (OR 1.39, 95% CI 1.06–1.83) were associated with CU (Figure 1). Sensitivity analyses confirmed these as robust determinants for prolonged disease. Previous studies in the general population and hospital care settings found that younger age was associated with faster remission and lower risk of CU development [4] and linked higher age at onset with longer disease duration [5, 6]. In line with previous studies high BMI also emerged as a determinant of CU [7, 8], which may be attributed to the ongoing inflammatory process induced by adipokines [7]. Finally, prednisolone prescription within 1 week after onset was associated with CU. A recent paediatric study (n = 155) reported that early steroid use and high disease activity predicted urticaria chronicity [9]. Although disease activity could not be investigated in our data, prednisolone prescriptions may reflect high severity. Interestingly, although prior studies considered infection an important trigger for AU in 37%–81% of cases [2], our study found no association. However, antibiotic prescriptions around onset were associated with shorter disease duration (< 4 weeks), though the association was not consistent across sensitivity analyses. Antibiotics are prescribed restrictively in the Netherlands and may only reflect more severe bacterial infections. Therefore, our findings likely provide an underestimation of the role of infections in acute urticaria. As this large JGPN-database includes data on GP consultations only, information on self-management is lacking. Additionally, in the absence of a diagnostic code distinguishing acute from chronic urticaria, the applied definitions, may have resulted in some inaccuracy and an underrepresentation of mild CU cases not seeking care. Also, the ICPC system does not distinguish spontaneous from inducible urticaria. In conclusion, this large primary care-based study provides valuable insights into the course of urticaria in an unselected population, demonstrating that most patients recover quickly within 1 week, while a notable 17% develop chronic urticaria. Higher age at onset, high BMI and prednisolone use in the first week were found to be determinants of long disease duration. In patients with symptoms persisting beyond 1 week and presenting with the found early determinants of CU a more proactive approach may be considered, as well as timely treatment escalation, referral and expectation management. All authors have made substantial contributions to conception, design or data acquisition of this study and have been involved in drafting or revising the manuscript. All authors have given final approval of the version to be published and agreed to be accountable for all aspects of the work. R.S. has full access to all the data in the study and takes responsibility for the integrity of the data. R.S. takes full responsibility for the accuracy of the data analysis. A.C. Knulst received institutional sponsoring for research or consultancy from: ALK, Thermofisher, Nutricia/Danone, DBV technologies, Novartis, EUROIMMUN, Stallergenes Greer. H.R. has received research funding from Novartis to support this work. She received institutional sponsoring for Research, consultancy or speakers fee outside the submitted work from Pharming and Novartis Pharma, Sanofi, Third Harmonic Bio, Abbvie, Leo Pharma. J.M.P.A. Van den Reek carried out clinical trials for AbbVie, Celgene, Almirall, and Janssen and has received speaking fees/attended advisory boards from Zoetis, AbbVie, Janssen, BMS, Almirall, LEO Pharma, Novartis, UCB and Eli Lilly and reimbursement for attending or chairing a symposium from Janssen, Pfizer, Celgene and AbbVie. All funding is not personal but goes to the independent research fund of the department of dermatology of Radboudumc Nijmegen, the Netherlands. The other authors declare no conflicts of interest. The data that support the findings of this study are available on request from the corresponding author, R.S.