Abstract
Purpose
The prevalence of chronic urticaria (CU) is increasing worldwide, and it imposes a major burden on patients. Few studies have evaluated the efficacy of second-line treatments of CU, particularly for patients being considered for costly third-line treatments such as omalizumab. We compared the efficacy and safety of second-line treatments of CU refractory to standard doses of nonsedating H1-antihistamines (nsAHs).
Methods
This 4-week, prospective, randomized, open-label trial divided patients into 4 treatment groups: 4-fold updosing of nsAHs, multiple combination of 4 nsAHs, switching to other nsAHs, and adjunctive H2-receptor antagonist. The clinical outcomes included urticaria control status, symptoms, and rescue medication use.
Results
This study included 109 patients. After 4 weeks of second-line treatment, urticaria was well-controlled, partly controlled, and uncontrolled in 43.1%, 36.7%, and 20.2% of patients, respectively. Complete control of CU was achieved in 20.4% of patients. Among the patients with high-dose nsAHs, the proportion with well-controlled status was higher compared to the patients who received standard doses (51.9% vs. 34.5%, P = 0.031). No significant difference was observed in the proportion of well-controlled cases between the updosing and combination treatment groups (57.7% vs. 46.4%, P = 0.616). However, increasing the dose of nsAHs 4-fold was associated with a higher rate of complete symptom control compared to multiple combination treatment with 4 nsAHs (40.0% vs. 10.7%, P = 0.030). Logistic regression analysis confirmed the higher efficacy of updosing of nsAHs for complete control of CU compared to the other treatment strategies (odds ratio, 0.180; P = 0.020).
Conclusions
In patients with CU refractory to standard doses of nsAHs, both updosing of nsAHs 4-fold and multiple combination treatment with 4 nsAHs increased the rate of well-controlled cases without causing significant adverse effects. Updosing of nsAHs is more effective for complete CU control than combination treatment.
Keywords: Chronic urticaria; histamine H1 antagonist, nonsedating; efficacy; safety
INTRODUCTION
Urticaria is characterized by wheals and/or angioedema. Acute urticaria is common, affecting almost 20% of the general population. Chronic urticaria (CU) persists for > 6 weeks.1,2,3,4 The prevalence of CU is increasing worldwide and is currently estimated at 0.1% in North America and 1.4% in Asia.5,6,7 The prevalence of CU varies among regions and is higher in Asia and Latin America than in Europe and North America.6 Due to its chronic and unpredictable disease course and frequent sleep disturbances, CU negatively impacts the quality of life (QOL), work productivity, and daily activities.7,8,9 The health status scores of CU patients were comparable to those of patients with coronary artery disease, while their subjective life satisfaction was lower than that of patients with respiratory allergy.3 Recent Korean population-based studies have found that CU imposes a major burden on patients due to the chronic disease course and the need for frequent healthcare visits.7,10,11,12,13,14,15,16 Therefore, a major goal of CU treatment is effective and complete symptom control.3,4
According to the international EAACI/GA2LEN/EuroDerm/APAAACI guidelines,3,4 a standard dose of second-generation nonsedating H1-antihistamines (nsAHs) is recommended as the first-line treatment of CU. However, up to 60% of CU patients do not respond adequately to first-line treatment within 2–4 weeks.5,17,18,19 When CU is not controlled with first-line treatment, second-line treatments, such as 4-fold updosing of nsAHs, are considered.19 The Korean CU guidelines recommend the 4-fold updosing of nsAHs when CU is not adequately controlled by a standard dose of nsAHs.1,2 However, Korean and international guidelines differ regarding the other second-line treatment options, such as treatment with multiple nsAHs (referred to hereafter as “combination treatment”). International guidelines do not recommend the use of combination treatment because of a lack of evidence of efficacy and differences in pharmacological properties among nsAHs.3,4 No randomized controlled trial has investigated the efficacy of combination treatment, whereas clinical studies and meta-analyses have provided evidence for the efficacy of nsAH updosing.5,19,20,21,22,23 However, the updosing of nsAHs is not licensed by the Korean Ministry of Food and Drug Safety and the associated costs are not covered by the Korean National Health Insurance Service. Consequently, Korean clinicians prefer to use combination treatment rather than the updosing of nsAHs. Anecdotal evidence suggests the effectiveness of combination treatment for refractory CU, despite the lack of scientific evidence.11,24 Therefore, the Korean guidelines conditionally recommend combination treatment given the very low evidence level, whereas updosing (low evidence level) is strongly recommended.1 Nevertheless, concerns still exist regarding the efficacy and safety of combination treatment.1,4
Other second-line treatments for CU, i.e., switching to other nsAHs and adjunctive H2-receptor antagonist (H2RA) treatment, are relatively ineffective.4 However, real-world evidence indicates that these treatments are still being prescribed.10 Moreover, 31.0%–69.9% of CU patients are treated with oral corticosteroids (OCSs) in combination with nsAHs, even though guidelines recommend that systemic steroids only be used for a short period to control exacerbation of CU. However, some clinicians still prefer to use OCSs in combination with nsAHs or switching to other nsAHs, rather than nsAH updosing or combination treatment.1,4,5,20 This discrepancy between guidelines and clinical practice has resulted in poor control of CU and long-term use of OCS, which may increase the disease burden and lead to serious adverse drug effects.18
There is an unmet clinical need regarding the efficacy and safety of second-line treatments of CU, particularly for patients being evaluated for possible costly third-line treatments, such as omalizumab. We compared efficacy and safety in second-line treatments for refractory CU to standard doses of nsAHs (i.e., updosing of nsAHs 4-fold, multiple combination treatment with 4 nsAHs, switching nsAHs, and adjunctive H2RA).
MATERIALS AND METHODS
Study design
This 4-week, prospective, randomized, open-label trial was conducted between August 2017 and August 2019 at 2 allergy clinics in university hospitals. The participants were randomized to 4 second-line treatment groups: 4-fold updosing of nsAHs, multiple combination of 4 nsAHs (high-dose nsAH groups), switching to other nsAHs, and adjunctive H2RA (standard-dose nsAH groups). Randomization was performed according to a balanced block design with a centrally generated randomization code. Blocks of 8 randomization numbers were allocated to each center. Antihistamines used in the trial were all second-generation antihistamines, including once a day of levocetirizine, cetirizine, fexofenadine, ebastine, and loratadine and twice a day of bepotastine, olopatadine, and azelastine. Cimetidine was used as H2RA.
During the study period, poor control or worsening of CU was treated with rescue medications, i.e., sedating H1-antihistamines (10 mg of hydroxyzine or 2 mg of chlorpheniramine) followed by OCSs (10 mg of prednisolone) for 3 consecutive days. The study design is presented in Fig. 1.
Fig. 1. Study design.
CU, chronic urticaria; nsAH, nonsedating H1-antihistamine; H2RA, H2-receptor antagonist; UAS7, urticaria activity score over 7 days, K-UCT, Korean version of the urticaria control test; CU-QOL, chronic urticaria-specific quality of life; VAS, visual analogue scale; AST, aspartate transaminase; ALT, alanine transaminase; Cr, creatinine.
Patients
We included outpatients aged > 18 years who had persistent urticaria (wheal formation or angioedema for > 6 weeks) and poor disease control despite treatment with at least 2 nsAHs for > 2 weeks. The control status of CU was determined by allergy specialists, as described in the evaluation of treatment efficacy below.11 Patients with other chronic dermatological diseases or liver enzyme levels > 2-fold higher than the reference ranges were excluded from the study.
At enrollment (visit 1, V1), clinical data were collected including age, sex, height, body weight, medical history (hypertension, diabetes mellitus, thyroid disease, asthma, allergic rhinitis, atopic dermatitis, food allergy, and drug allergy), history of adverse reaction to nsAHs, onset age of CU, disease duration, and response to previous medications. Body mass index (BMI) was calculated as Weight/Height2. We also recorded laboratory parameters, including the complete blood count (neutrophils, eosinophils, and lymphocytes) and aspartate transaminase (AST), alanine transaminase (ALT), creatinine, and total immunoglobulin E (IgE) levels. The patients were divided into normal and high total IgE level (0–114 and > 114 kU/L, respectively) groups according to previous studies.25,26,27,28 The autologous serum skin test was also performed according to the method described in the EAACI/GA2LEN task force consensus report.29
Evaluation of treatment efficacy
The primary endpoint was urticaria control status after 4 weeks of second-line treatment. Urticaria control state was categorized by physicians as well-controlled, partly controlled, or uncontrolled.11 CU was considered well-controlled if patients on medication had no itchy wheals, partly controlled if the urticarial symptoms were reduced but not fully controlled, and uncontrolled if the urticarial symptoms were not controlled by medications.
The secondary endpoints were patient-reported outcomes (PROs) including the urticaria activity score over 7 days (UAS7), score on the Korean version of the urticaria control test (K-UCT; originally developed in German), chronic urticaria-specific quality of life (CU-QOL) score, visual analogue scale (VAS) score, and rescue medications used.8,11,15,24,30 The UAS7 was calculated by summing the itch severity score (0, none; 1, mild; 2, moderate; 3, severe) and wheal score (0, no wheals; 1, 1–19 wheals; 2, 20–50 wheals; 3, > 50 wheals). A UAS7 of 0 indicated complete symptom control. The CU-QOL consists of 17 items distributed over 4 domains: urticarial symptoms, emotional distress, food and environmental distress, and stigma. Rescue medication use was analyzed in terms of frequency, cumulative dose, and the number of participants who used such medications (i.e., H1-antihistamines or OCS).
Safety profile
Adverse reactions to nsAHs were recorded at V1 and V2, including drowsiness, dry mouth, voiding difficulty, weight gain, and abnormal serum creatinine and liver function tests.
Ethical issues
This study was approved by Ajou and Hallym University Hospital Institutional Review Boards (AJIRB-MED-OBS-17-173 and HDT2017-08-002). All patients provided written informed consent at the time of enrollment.
Statistical analysis
Continuous variables are presented as means ± standard deviations, and categorical variables as numbers (percentages). Clinical characteristics and treatment responses were compared between high- and standard-dose groups using Student’s t-test for continuous data and the χ2 test for categorical data. The 4 groups were compared using analysis of variance and the χ2 test, with P values adjusted according to the false discovery rate using R software (version 4.1.0; R Foundation for Statistical Computing, Vienna, Austria). Changes in symptom scores after 4 weeks of second-line treatment were analyzed using generalized estimating equations. Associations were analyzed using Pearson’s correlation for continuous data and logistic regression for categorical data. All tests were 2-sided, and P < 0.05 was considered significant. Statistical analyses were conducted using SPSS software (version 18.0; IBM Corp., Armonk, NY, USA).
RESULTS
Study participants
In total, 114 patients participated in this study, 11 of whom could not complete it because of adverse reactions (n = 2) or insufficient efficacy (n = 9). Available data were used in the full data analysis, and a total of 109 patients’ V2 data were included in the analysis (Supplementary Fig. S1). The mean age of the participants was 39.8 ± 12.7 years, and 56.0% were female. The onset age of CU was 37.6 ± 13.5 years, and the mean disease duration was 25.2 months. In total, 26 (23.9%) patients did not respond to standard doses of nsAHs, whereas the remaining 83 (76.1%) exhibited insufficient improvement. Table 1 presents the CU symptom scores and demographic characteristics of the participants. Most clinical characteristics showed no statistically significant differences among groups, including age, sex, urticaria duration, and laboratory parameters (Table 1).
Table 1. Comparison of clinical characteristics by second-line treatments.
| Variables | Total (n = 109) | High dose of nsAHs | Standard dose of nsAHs | P value | |||
|---|---|---|---|---|---|---|---|
| Updosing 4 folds (n = 26) | Multiple combination (n = 28) | Changing nsAHs (n = 28) | Add-on H2RA (n = 27) | ||||
| Age (yr) | 39.8 ± 12.7 | 35.8 ± 12.4 | 41.3 ± 13.2 | 40.3 ± 12.5 | 41.6 ± 12.5 | 0.308 | |
| Female | 61 (56.0) | 9 (34.6) | 14 (50.0) | 15 (53.6) | 10 (37.0) | 0.816 | |
| BMI (kg/m2) | 23.7 ± 3.5 | 22.4 ± 3.9 | 23.3 ± 3.4 | 24.6 ± 3.4 | 24.5 ± 2.8 | 0.054 | |
| Hypertension | 11 (10.1) | 0 (0) | 1 (3.6) | 6 (21.4) | 4 (14.8) | 0.031 | |
| Diabetes | 2 (1.8) | 0 (0) | 1 (3.6) | 0 (0) | 1 (3.7) | 0.532 | |
| Thyroid disease | 4 (3.7) | 1 (3.8) | 2 (7.1) | 1 (3.6) | 0 (0) | 0.346 | |
| Previous allergic disease | |||||||
| Bronchial asthma | 2 (1.8) | 1 (3.8) | 0 (0) | 1 (3.6) | 0 (0) | 0.509 | |
| Allergic rhinitis | 50 (45.9) | 15 (57.7) | 7 (25.0) | 13 (46.4) | 15 (55.6) | 0.689 | |
| Atopic dermatitis | 3 (2.8) | 0 (0) | 1 (3.6) | 1 (3.6) | 1 (3.7) | 0.442 | |
| Food allergy | 5 (4.6) | 0 (0) | 2 (7.1) | 1 (3.6) | 2 (7.4) | 0.316 | |
| Drug allergy | 5 (4.6) | 0 (0) | 2 (7.1) | 2 (7.1) | 1 (3.7) | 0.555 | |
| Onset age of CU (yr) | 37.6 ± 13.5 | 32.4 ± 13.9 | 39.9 ± 13.3 | 37.7 ± 12.8 | 40.1 ± 13.3 | 0.132 | |
| Duration of CU (mon) | 25.2 ± 54.2 | 39.7 ± 75.0 | 15.6 ± 24.6 | 29.8 ± 69.5 | 16.4 ± 27.3 | 0.303 | |
| Previous treatment response | 0.897 | ||||||
| No response | 26 (23.9) | 6 (23.1) | 7 (25.0) | 6 (21.4) | 7 (25.9) | ||
| Insufficient efficacy | 83 (76.1) | 20 (76.9) | 21 (75.0) | 22 (78.6) | 20 (74.1) | 0.897 | |
| ASST positivity (n = 82) | 30 (27.5) | 10 (47.6) | 8 (34.8) | 6 (27.3) | 6 (37.5) | 0.385 | |
| Total IgE (kU/L) | 245.3 ± 374.0 | 178.9 ± 157.9 | 190.4 ± 184.9 | 343.4 ± 592.3 | 264.4 ± 372.6 | 0.335 | |
| Total IgE group | 0.828 | ||||||
| Normal (0–114) | 55 (50.5) | 14 (53.8) | 14 (50.0) | 13 (46.4) | 14 (51.9) | ||
| High (> 114) | 54 (49.5) | 12 (46.2) | 14 (50.0) | 15 (53.6) | 13 (48.1) | ||
| WBC (%) | |||||||
| Neutrophil | 59.0 ± 8.3 | 59.3 ± 8.2 | 58.2 ± 7.8 | 60.3 ± 8.5 | 58.5 ± 8.9 | 0.969 | |
| Lymphocyte | 30.4 ± 7.9 | 30.1 ± 9.4 | 30.5 ± 6.6 | 29.9 ± 7.6 | 30.9 ± 8.2 | 0.969 | |
| Eosinophil | 2.4 ± 1.8 | 1.9 ± 1.4 | 2.8 ± 2.1 | 2.2 ± 1.5 | 2.8 ± 2.0 | 0.198 | |
| AST (IU/L) | 20.8 ± 6.9 | 19.1 ± 4.1 | 22.9 ± 9.7 | 19.1 ± 5.0 | 22.2 ± 6.6 | 0.069 | |
| ALT (IU/L) | 22.7 ± 13.6 | 19.2 ± 9.3 | 23.3 ± 13.3 | 23.3 ± 15.4 | 25.0 ± 15.5 | 0.461 | |
| Creatinine (mg/dL) | 0.8 ± 0.2 | 0.8 ± 0.2 | 0.8 ± 0.2 | 0.8 ± 0.2 | 0.8 ± 0.2 | 0.569 | |
| CU symptom score | |||||||
| UAS7 (0–42) | 23.3 ± 9.5 | 22.9 ± 8.3 | 22.0 ± 10.4 | 23.0 ± 9.5 | 25.4 ± 9.7 | 0.591 | |
| K-UCT (0–16) | 7.1 ± 3.0 | 8.2 ± 3.0 | 7.1 ± 3.0 | 6.9 ± 2.9 | 6.3 ± 2.9 | 0.132 | |
| CU-QOL (0–100) | 63.3 ± 20.0 | 69.2 ± 18.4 | 64.1 ± 22.2 | 59.3 ± 20.0 | 60.8 ± 18.5 | 0.275 | |
| Patient’s VAS (0–100) | 57.1 ± 28.0 | 51.5 ± 28.0 | 49.4 ± 27.5 | 60.8 ± 31.3 | 66.7 ± 22.3 | 0.074 | |
Values are presented as number (%) or mean ± standard deviation. P values were calculated by linear-by-linear association test in categorical variables and by analysis of variance in continuous variables.
ALT, alanine transaminase; ASST, autologous serum skin test; AST, aspartate transaminase; BMI, body mass index; CU, chronic urticaria; CU-QOL, chronic urticaria-specific quality of life; H2RA, H2-receptor antagonist; IgE, immunoglobulin E; K-UCT, Korean version of urticaria control test; nsAH, nonsedating H1-antihistamine; UAS7, urticaria activity score over 7 days; VAS, visual analogue scale; WBC, white blood cell.
Outcomes after 4 weeks of second-line treatment
Urticaria was well-controlled, partly controlled, and uncontrolled in 43.1%, 36.7%, and 20.2% of patients after 4 weeks of treatment, respectively (Fig. 2). There were significant differences in urticaria control status among all 4 groups (P = 0.007; Fig. 2A), and between the high- and standard-dose groups; the proportion of well-controlled cases was significantly higher in the high-dose group than in the standard-dose group at V2 (51.9% vs. 34.5%; P = 0.031; Fig. 2B). However, there was no significant difference in urticaria control status between the nsAH updosing and combination treatment groups (57.7% vs. 46.4%, P = 0.616; Fig. 2A).
Fig. 2. Urticaria control status, as assessed by physicians after 4 weeks of treatment. Comparisons among the 4 treatment groups: (A) 4-fold updosing of nsAHs, combination treatment with 4 nsAHs, switching to other nsAHs, and adjunctive H2RA and (B) high- and standard-dose nsAH groups are presented. P values were calculated by the χ2 test after adjustment based on the false discovery rate (R 4.1.0; R Foundation for Statistical Computing, Vienna, Austria) to correct bias during multiple comparisons.
nsAH, nonsedating H1-antihistamine; H2RA, H2-receptor antagonist.
*P valuescalculated using the linear-by-linear association test.
Complete symptom control (i.e., UAS7 = 0 at V2) was achieved in 21 (20.4%) patients after 4 weeks of treatment. The rate of complete urticaria control was higher in the nsAH updosing group than in the combination treatment group (P = 0.030; Fig. 3A), but there was no significant difference between the high- and standard-dose groups (P = 0.292; Fig. 3B).
Fig. 3. Proportion of cases achieving complete urticaria control (UAS7 = 0) after 4 weeks of treatment. Comparisons among the 4 treatment groups: (A) 4-fold updosing of nsAHs, combination treatment with 4 nsAHs, switching to other nsAHs, and adjunctive H2RA and (B) high- and standard-dose nsAH groups are presented. P values were calculated using the χ2 test after adjustment based on the false discovery rate (R 4.1.0; R Foundation for Statistical Computing, Vienna, Austria) to correct bias during multiple comparisons.
nsAH, nonsedating H1-antihistamine; H2RA, H2-receptor antagonist; UAS, urticaria activity score.
*P values calculated using the linear-by-linear association test.
**P values calculated using the χ2 test.
Next, we compared the CU symptom scores and changes therein after 4 weeks of second-line treatment. All treatments significantly improved the CU-related PROs, including the UAS7, K-UCT, CU-QOL, and VAS scores (Table 2), and there were no differences in the degree of improvement among the 4 groups (Supplementary Fig. S2).
Table 2. Comparison of CU symptom scores after 4 weeks of second-line treatments.
| Variables | UAS7 (0–42) | K-UCT (0–16) | CU-QOL (0–100) | Patient’s VAS (0–100) | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Visit 1 | Visit 2 | P value | Visit 1 | Visit 2 | P value | Visit 1 | Visit 2 | P value | Visit 1 | Visit 2 | P value | ||
| High dose nsAHs | |||||||||||||
| Updosing 4 folds (n = 25) | 23.2 ± 8.3 | 10.4 ± 12.6 | < 0.001 | 8.2 ± 3.1 | 10.0 ± 4.6 | 0.030 | 68.2 ± 18.0 | 78.6 ± 26.5 | 0.006 | 53.1 ± 27.3 | 31.7 ± 30.1 | 0.002 | |
| Multiple combination (n = 28) | 22.0 ± 10.4 | 16.3 ± 11.3 | 0.012 | 7.1 ± 3 | 9.4 ± 3.9 | < 0.001 | 64.1 ± 22.2 | 74.6 ± 22.7 | 0.005 | 49.4 ± 27.5 | 36.1 ± 30.2 | 0.020 | |
| Standard dose nsAHs | |||||||||||||
| Changing nsAHs (n = 28) | 23.0 ± 9.5 | 17.0 ± 12.1 | 0.007 | 6.9 ± 2.9 | 9.1 ± 3.8 | 0.002 | 59.3 ± 20.0 | 76.5 ± 18.8 | < 0.001 | 60.8 ± 31.3 | 38.4 ± 28.2 | 0.001 | |
| Add-on H2RA (n = 27) | 25.4 ± 9.7 | 15.3 ± 12.6 | 0.001 | 6.3 ± 2.9 | 9.3 ± 3.8 | 0.001 | 60.8 ± 18.5 | 75.9 ± 21.5 | 0.001 | 66.7 ± 22.3 | 36.3 ± 28.8 | < 0.001 | |
Values are presented as mean ± standard deviation. P values were calculated by paired t-test between visit 1 and 2.
CU, chronic urticaria; CU-QOL, chronic urticaria-specific quality of life; H2RA, H2-receptor antagonist; K-UCT, Korean version of urticaria control test; nsAH, non-sedating H1-antihistamine; UAS7, urticaria activity score over 7 days; VAS, visual analogue scale.
Parameters associated with urticaria control status after 4 weeks of second-line treatment
Baseline clinical characteristics were compared according to the therapeutic response after 4 weeks of treatment (Table 3). There were significant differences in CU duration, total IgE level, CU symptom scores, and treatment types. Next, logistic regression analysis was performed to identify clinical parameters associated with well-controlled urticaria after 4 weeks of treatment (Table 4). No parameters, except the K-UCT score, showed an association with well-controlled status. Additionally, there was no significant difference in the proportion of well-controlled cases between the nsAH updosing and combination treatment groups (odds ratio [OR], 0.636; P = 0.409). The initial K-UCT score was significantly associated with successful treatment outcomes, indicating that the lower initial symptom burden was associated with the well-controlled state. The other clinical and laboratory parameters analyzed in previous studies27 were not associated with the well-controlled state of CU in the present study.
Table 3. Comparisons of baseline clinical characteristics according to therapeutic response after 4-week treatment.
| Variables | Well-controlled (n = 47) | Partly controlled (n = 40) | Uncontrolled (n = 22) | P value | |
|---|---|---|---|---|---|
| Age | 38.0 ± 13.3 | 40.6 ± 11.4 | 42.1 ± 13.6 | 0.404 | |
| Female | 28 (59.6) | 21 (52.5) | 12 (54.5) | 0.613* | |
| BMI (kg/m2) | 23.1 ± 3.6 | 24.0 ± 3.3 | 24.5 ± 3.6 | 0.230 | |
| Onset age of CU (yr) | 36.7 ± 13.5 | 38.8 ± 12.0 | 37.4 ± 16.3 | 0.787 | |
| Duration of CU (mon) | 16.1 ± 27.1 | 19.4 ± 28.6 | 55.1 ± 104.0 | 0.013 | |
| ASST positivity (n = 81) | 15 (38.5) | 11 (44.0) | 4 (22.2) | 0.341* | |
| Total IgE (kU/L) | 172.7 ± 152.8 | 205.6 ± 201.8 | 472.3 ± 723.6 | 0.005 | |
| Normal (0–114) | 25 (53.2) | 21 (52.5) | 9 (40.9) | 0.397* | |
| High (> 114) | 22 (46.8) | 19 (47.5) | 13 (59.1) | ||
| CU symptom score | |||||
| UAS7 (0–42) | 21.3 ± 8.9 | 23.3 ± 9.9 | 27.7 ± 8.8 | 0.032 | |
| K-UCT (0–16) | 8.3 ± 2.5 | 6.6 ± 3.2 | 5.6 ± 2.9 | 0.001 | |
| CU-QOL (0–100) | 67.8 ± 19.8 | 63.5 ± 19.8 | 53.3 ± 17.6 | 0.018 | |
| Patient’s VAS (0–100) | 53.7 ± 26.2 | 52.7 ± 30.1 | 72.5 ± 23.3 | 0.014 | |
| Treatment arms | 0.007* | ||||
| Changing nsAH | 9 (19.1) | 6 (15.0) | 13 (59.1) | ||
| Add-on H2RA | 10 (21.3) | 15 (37.5) | 2 (9.1) | ||
| Combined 4 nsAHs | 13 (27.7) | 12 (30.0) | 3 (13.6) | ||
| Updosing 4 folds | 15 (31.9) | 7 (17.5) | 4 (18.2) | ||
| Treatment groups | |||||
| High dose nsAHs | 28 (59.6) | 19 (47.5) | 7 (31.8) | 0.031* | |
| Standard dose nsAHs | 19 (40.4) | 21 (52.5) | 15 (68.2) | ||
Values are presented as number (%) or mean ± standard deviation.
ASST, autologous serum skin test; BMI, body mass index; CU, chronic urticaria; CU-QOL, chronic urticaria-specific quality of life; H2RA, H2-receptor antagonist; IgE, immunoglobulin E; K-UCT, Korean version of urticaria control test; nsAH, nonsedating H1-antihistamine; UAS7, urticaria activity score over 7 days; VAS, visual analogue scale.
*P value was analyzed by linear-by-linear association test and other P values by analysis of variance.
Table 4. Parameters associated with the well-controlled state after 4 weeks of second-line treatments.
| Variables (n = 109) | OR | 95% CI | P value | |
|---|---|---|---|---|
| Age (yr) | 0.980 | 0.951–1.011 | 0.203 | |
| Sex (female) | 1.295 | 0.601–2.789 | 0.509 | |
| BMI (kg/m2) | 0.909 | 0.808–1.021 | 0.108 | |
| Duration of CU (mon) | 0.990 | 0.981–1.003 | 0.169 | |
| ASST positivity (n = 82) | 1.167 | 0.474–2.869 | 0.737 | |
| Total IgE (kU/mL) | 0.999 | 0.997–1.000 | 0.106 | |
| Total IgE group | ||||
| Normal (0–114) | Ref. | |||
| High (> 114) | 0.825 | 0.386–1.763 | 0.619 | |
| CU symptom score at visit 1 | ||||
| UAS7 (0–42) | 0.973 | 0.923–1.025 | 0.306 | |
| K-UCT (0–16) | 1.424 | 1.128–1.798 | 0.003 | |
| CU-QOL (0–100) | 0.992 | 0.964–1.021 | 0.602 | |
| Patient’s VAS (0–100) | 1.017 | 0.997–1.039 | 0.100 | |
| Treatment types | 0.139 | |||
| Updosing 4 folds | Ref. | |||
| Multiple combination | 0.636 | 0.217–1.863 | 0.409 | |
| Standard dose nsAHs | 0.387 | 0.149–1.007 | 0.052 | |
ASST, autologous serum skin test; BMI, body mass index; CI, confidential interval; CU, chronic urticaria; CU-QOL, chronic urticaria-specific quality of life; IgE, immunoglobulin E; K-UCT, Korean version of urticaria control test; nsAH, nonsedating H1-antihistamine; OR, odds ratio; UAS7, urticaria activity score over 7 days; VAS, visual analogue scale.
The logistic regression analysis according to the nsAH dose groups showed that the serum total IgE level was significantly associated with the well-controlled state when the patients were treated with the standard doses of nsAHs (OR, 0.994; P = 0.025; Supplementary Table S1). Patients with a high total IgE showed a lower likelihood of well-controlled CU compared to those with a normal total IgE level (OR, 0.202; P = 0.011) among those treated with standard doses of nsAHs. Younger age was significantly associated with well-controlled CU (OR, 0.938; P = 0.035), whereas low BMI showed a trend toward an association with well-controlled CU (OR, 0.786; P = 0.062). However, these associations were not observed in patients treated with high-dose nsAHs (Supplementary Table S2). Patients with a high total IgE level had a higher likelihood of well-controlled CU compared to those with a normal total IgE level (OR, 2.919; P = 0.058), while age and BMI were not significantly associated with well-controlled CU in these patients. In both nsAH dose groups, outcomes did not differ by treatment regimen.
Logistic regression analysis was performed to identify clinical parameters associated with complete symptom control (UAS7 = 0 at V2; Table 5). Unlike the results for well-controlled CU status, a higher rate of complete control was seen in the nsAH updosing group compared to the combination treatment group (OR, 0.180; P = 0.020) and patients receiving standard doses of nsAHs (OR, 0.293; P = 0.025). CU symptom scores showed significant associations with complete symptom control. Additionally, logistic regression analysis according to the nsAH dose groups revealed no significant associations of clinical parameters with complete urticaria control, except in the nsAH updosing group relative to the other second-line treatments (OR, 0.180, P = 0.020, results were not shown).
Table 5. Parameters associated with the complete control state (UAS7 = 0).
| Variables (n = 108) | OR | 95% CI | P value | |
|---|---|---|---|---|
| Age (yr) | 0.978 | 0.941–1.016 | 0.247 | |
| Sex (female) | 1.863 | 0.691–5.026 | 0.219 | |
| BMI (kg/m2) | 1.003 | 0.877–1.148 | 0.959 | |
| Duration of CU (mon) | 1.001 | 0.993–1.009 | 0.857 | |
| ASST positivity (n = 81) | 2.304 | 0.778–6.824 | 0.132 | |
| Total IgE (kU/mL) | 1.000 | 0.999–1.001 | 0.964 | |
| Total IgE group | ||||
| Normal (0–114) | Ref. | |||
| High (> 114) | 1.000 | 0.392–2.551 | 1.000 | |
| CU symptom score at visit 1 | ||||
| UAS7 (0–42) | 0.974 | 0.925–1.026 | 0.329 | |
| K-UCT (0–16) | 1.299 | 1.087–1.553 | 0.004 | |
| CU-QOL (0–100) | 1.031 | 1.002–1.061 | 0.036 | |
| Patient’s VAS (0–100) | 0.983 | 0.967–1.000 | 0.050 | |
| Treatment types | 0.025 | |||
| Updosing 4 folds | Ref. | |||
| Multiple combination | 0.180 | 0.043–0.760 | 0.020 | |
| Standard dose nsAHs | 0.293 | 0.100–0.858 | 0.025 | |
ASST, autologous serum skin test; BMI, body mass index; CI, confidential interval; CU, chronic urticaria; CU-QOL, chronic urticaria-specific quality of life; IgE, immunoglobulin E; K-UCT, Korean version of urticaria control test; nsAH, nonsedating H1-antihistamine; OR, odds ratio; UAS7, urticaria activity score over 7 days, VAS, visual analogue scale.
Serum total IgE levels according to control status
The initial serum total IgE level significantly differed by urticaria control status (well-controlled, partly controlled, and uncontrolled; Fig. 4A). No significant difference was observed in serum total IgE according to control status in the high-dose group (well-controlled, 213.8 ± 170.0 kU/L; partly controlled, 142.0 ± 182.7 kU/L; uncontrolled, 185.1 ± 134.6 kU/L; P = 0.375; Fig. 4B). However, significant differences were observed in total IgE levels according to control status in the standard-dose group (well-controlled, 112.1 ± 99.2 kU/L; partly controlled, 263.2 ± 205.1 kU/L; uncontrolled, 606.3 ± 846.9 kU/L; P = 0.011; Fig. 4C). The correlation analysis between the initial serum total IgE level and UAS7 scores at V2 showed similar associations (Fig. 4D-F), particularly in patients treated with standard doses of nsAHs (Fig. 4F; r = 0.334; P = 0.013).
Fig. 4. Comparison of serum total IgE level between well-controlled and partly/uncontrolled chronic urticaria cases after 4 weeks of second-line treatment in all patients (A), the high-dose nsAH group (B), and the standard-dose nsAH group (C). Correlation between serum total IgE level and UAS7 score at visit 2 in all patients (D), the high-dose nsAH group (E), and the standard-dose nsAH group (F).
IgE, immunoglobulin E; nsAH, nonsedating H1-antihistamine; UAS7, urticaria activity score over 7 days.
Rescue medication use
Rescue medication use was analyzed in terms of frequencies, cumulative doses, and proportions of patients requiring such medications. There were no significant differences in the use of rescue H1-antihistamines among the 4 treatment groups (Table 6). Comparison of the nsAH dose groups showed a lower frequency of use of sedating H1-antihistamines in the high- than low-dose group (0.69 ± 0.87 vs. 1.27 ± 2.35; P = 0.086; Supplementary Fig. S3A). However, no significant differences were observed in cumulative dose between the high- and low-dose groups (60.9 ± 104.7 vs. 74.6 ± 96.0; P = 0.480; Supplementary Fig. S3B). There were no significant differences in the proportion of patients using sedating H1-antihistamines as rescue medications between the high- and standard-dose nsAH groups (50.0% vs. 56.6%, respectively; P = 0.502).
Table 6. Use of rescue medications during the study period by the 4 study groups.
| Variables | High dose nsAHs | Standard dose nsAHs | P value | |||
|---|---|---|---|---|---|---|
| Updosing 4 folds (n = 26) | Multiple combination (n = 28) | Changing nsAHs (n = 28) | Add-on H2RA (n = 27) | |||
| Rescue H1-antihistamine | ||||||
| Frequency | 0.69 ± 0.93 | 0.68 ± 0.82 | 1.61 ± 3.01 | 0.93 ± 1.33 | 0.177 | |
| Cumulative dose | 63.46 ± 91.87 | 58.57 ± 116.96 | 73.21 ± 90.64 | 75.93 ± 102.97 | 0.911 | |
| No. of subjects | 13 (54.2) | 12 (46.2) | 17 (60.7) | 13 (52.0) | 0.759 | |
| Rescue OCS | ||||||
| Frequency | 0.42 ± 0.90 | 0.79 ± 1.75 | 0.79 ± 1.73 | 0.33 ± 0.56 | 0.471 | |
| Cumulative dose | 16.54 ± 39.08 | 21.07 ± 39.28 | 22.50 ± 34.06 | 21.85 ± 40.67 | 0.941 | |
| No. of subjects | 7 (29.2) | 10 (38.5) | 9 (32.1) | 8 (32.0) | 0.912 | |
Values are presented as number (%) or mean ± standard deviation.
H2RA, H2-receptor antagonist; nsAHs, nonsedating H1-antihistamines; OCS, oral corticosteroid.
The rate of use of rescue OCSs did not show a significant difference among the 4 treatment groups (Table 6). No significant difference was observed between the high- and standard-dose groups in OCS use rate (34.0% vs. 32.1%; P = 0.836). Similar results were obtained in the comparison of high- and standard-dose groups in terms of the frequency of OCS use (0.61 ± 1.40 vs. 0.56 ± 1.30; P = 0.855) and cumulative OCS dose (18.89 ± 38.88 vs. 22.18 ± 37.10; P = 0.652).
Safety profile
After 4 weeks of second-line treatment, 18 (16.7%) patients experienced adverse events, including drowsiness (27.6%), dry mouth (20.7%), dyspepsia (13.8%), weight gain (13.8%), and frequent urination (10.3%). There were no significant differences in the frequency of adverse events among all 4 treatment groups (11.5%, 18.5%, 14.3%, and 22.2% in the updosing, combination treatment, switching treatment, and adjunctive H2RA groups, respectively; P = 0.396) or between the 2 dose groups (15.1% and 18.2% in the high- and standard-dose groups, respectively; P = 0.667). Additionally, no patients exhibited laboratory abnormalities, including in the AST, ALT, or creatinine level, after 4 weeks of second-line treatment.
DISCUSSION
In this randomized, open-label trial, we compared the efficacy of second-line treatments for CU refractory to standard doses of nsAHs. The second-line treatments included high-dose (4-fold updosing of nsAHs and combination treatments of 4 nsAHs) and standard-dose (switching to other nsAHs and adjunctive H2RA) nsAHs. After 4 weeks of second-line treatment, 43.1% of patients achieved well-controlled status, while in the remaining patients, the disease was partly controlled (36.7%) or uncontrolled (20.2%). In the high-dose group, the proportion of well-controlled cases was higher compared to the standard-dose group (51.9% vs. 34.5%, P = 0.031). High doses of nsAHs were well-tolerated, and no significant differences were observed in adverse events or laboratory abnormalities after 4 weeks of treatment relative to baseline. A previous meta-analysis showed that the updosing of nsAHs significantly improved the control of pruritus in CU patients, but not the wheal number. However, definitive conclusions could not be drawn because the meta-analysis had certain limitations, such as significant heterogeneity among the included studies.19 However, another study reported good CU control outcomes with long-term updosing of nsAHs and multiple combination treatment.31 Our data support the efficacy of high-dose nsAHs for controlling CU: treatment with high-dose nsAHs for 1 month was associated with well-controlled CU in almost half of the patients, with no significant adverse reactions. One-third of CU patients treated with standard doses of nsAHs also achieved well-controlled CU status. These findings suggest that the considering time point for the use of omalizumab should be reconsidered. Current international guidelines recommend the use of omalizumab if CU is uncontrolled after 2–4 weeks of nsAH treatment. In patients refractory to standard doses of nsAHs, CU may be controlled with 1 month of nsAH treatment, particularly when higher doses are used. Similar efficacy was observed between our nsAH updosing and multiple combination treatment groups in terms of CU control, whereas a higher rate of complete control was observed in the updosing group than in the combination treatment group; there were no significant differences in adverse events.
In addition to the nsAH dose, a higher baseline total IgE level was significantly associated with CU control status after 4 weeks of nsAH treatment, particularly for CU patients treated with standard doses of nsAHs. In these patients, the baseline total IgE level was negatively associated with well-controlled CU status. Additionally, patients with a high total IgE level had a lower likelihood of well-controlled CU status during standard-dose nsAH treatment, whereas control was improved with high doses of nsAHs. Therefore, patients with a high baseline total IgE level may be poorly responsive to standard doses of nsAHs; for such patients, a high dose of nsAHs should be considered. Recent studies have proposed 2 pathogenic mechanisms for chronic spontaneous urticaria (CSU): type I and type IIb autoimmune mechanisms. A higher serum total IgE level is characteristic of type I autoimmune CSU, and a good response to nsAHs or omalizumab. By contrast, type IIb CSU is similar to autoimmune diseases.32 Our findings also suggest that, in CU patients with a higher total IgE level, the disease may be better controlled with high rather than standard nsAH doses.
Similar to the total IgE level, BMI was negatively associated with urticaria control in the standard-dose group, suggesting that obese CU patients are less likely to respond to the standard doses of nsAHs. We hypothesized that these results may be due to the effect of BMI on the effective medication dose: nsAH levels may be lower in obese CU patients than in CU patients with a normal or low BMI, which could explain the differences in treatment efficacy according to BMI seen with standard-dose treatment. The lack of difference in treatment efficacy according to BMI at high nsAH doses could be explained by such doses being sufficient regardless of BMI. In a previous study, BMI showed an inconsistent association with responsiveness to nsAHs.27 However, limited information was available regarding the nonresponse to nsAHs, and the exact nsAH dose was not known in most cases. In our study, BMI was negatively associated with treatment outcomes when standard doses of nsAHs were used. In addition to the total IgE level and BMI, an initial worse symptom score was associated with a poor response to nsAH treatment, similar to previous studies.27
Taken together, these findings suggest that high doses of nsAHs are associated with better CU control compared to standard doses, while no significant differences were observed between the nsAH updosing 4-fold and multiple combination treatment groups. CU patients with a higher total IgE level (> 114 kU/L), older age, or higher BMI may be less responsive to standard doses of nsAHs. Such patients should be considered for high-dose treatment, i.e., nsAH updosing or combination treatment.
Most recent randomized controlled trials of CU treatments have focused on third-line treatments, particularly omalizumab.33 Omalizumab is effective for the treatment of CU cases refractory to previous treatments, although it is prohibitively expensive. By contrast, few clinical trials have evaluated second-line treatments for CU patients refractory to the standard doses of nsAHs. To the best of our knowledge, this is the first prospective, randomized, head-to-head comparison of various nsAH treatment regimens, particularly 4-fold updosing of nsAHs and combination treatment with 4 nsAHs. There was no significant difference in the proportion of well-controlled CU cases between the updosing and combination treatment groups, while the rate of complete CU control was higher in the former group. Additionally, 51.9% of CU patients refractory to standard-dose nsAHs responded to 4 weeks of treatment with high-dose nsAHs, suggesting that clinicians should consider the use of high-dose nsAHs before omalizumab, which is effective but expensive.
The international EAACI/GA2LEN/EuroDerm/APAAACI guideline does not recommend nsAH combination treatment because of insufficient evidence regarding its efficacy and safety. However, our study supports the effectiveness of combination treatment for CU control in patients refractory to standard doses of nsAHs without safety issues. Additionally, 4-fold updosing of nsAHs is safe and effective. The discriminated point between these 2 treatments is the superiority of complete symptom control (i.e., no urticaria after 4 weeks of treatment) in 4-fold updosing of nsAH than combination treatment. The updated EAACI/GA2LEN/EuroDerm/APAAACI international guideline defined the treatment goal of CU as urticarial remission and complete symptom control (continuous UAS7 = 0).3 To achieve this goal, 4-fold updosing of nsAHs has been recommended as a preferable second-line treatment. However, considering the reimbursement and licensing problems associated with updosing of nsAHs, combination treatment may be more feasible for achieving well-controlled status. Nevertheless, updosing remains the ideal treatment regimen for CU patients refractory to standard doses of nsAHs.
There were some limitations to the present study, including the small sample size and short study duration. The relatively small number of patients in each group may explain the lack of statistically significant differences among them. Additionally, a 4-week study period is insufficient to evaluate the efficacy of second-line treatments in some patients. Nevertheless, we compared the efficacy and safety of various nsAH treatments in this prospective randomized trial, particularly nsAH updosing and combination treatment. Although the study topic may not be of interest to pharmaceutical companies, it offers interestto clinicians. Additionally, we analyzed clinical parameters that predicted CU control according to nsAH dose (standard or high).
In conclusion, high-dose nsAHs, via updosing or combination treatment, were effective for controlling CU in patients refractory to standard doses, with no adverse effects. However, updosing was more effective than combination treatment for complete CU control. Additionally, CU patients who are old or obese, or have a high serum total IgE level, would be poorly responsive to standard doses of nsAHs; such patients should be considered for high-dose treatment via updosing or combination treatment.
ACKNOWLEDGMENTS
This study was supported by a grant from the Korean Academy of Asthma, Allergy and Clinical Immunology and a grant from the National Research Foundation of Korea (NRF-2022R1A2C2006607).
Footnotes
Disclosure: There are no financial or other issues that might lead to conflicts of interest.
SUPPLEMENTARY MATERIALS
Parameters associated with well-controlled state treated by the standard dose of antihistamines
Parameters associated with well-controlled state treated by the high dose of antihistamines
Consort flow diagram of the study, including enrollment, allocation, follow-up, and analysis.
Comparison of the degree of improvement in chronic urticaria symptom scores after 4 weeks of treatment among the 4 treatment groups: (A-D) 4-fold updosing of nsAHs, combination treatment with 4 nsAHs, switching to other nsAHs, and adjunctive H2RA; and (E-H) high- and standard-dose nsAH groups. P values were calculated using generalized estimating equations.
Comparison of rescue medication use between the high- and standard-dose antihistamine groups: frequency (A) and cumulative doses (B) of rescue H1-antihistamine.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Parameters associated with well-controlled state treated by the standard dose of antihistamines
Parameters associated with well-controlled state treated by the high dose of antihistamines
Consort flow diagram of the study, including enrollment, allocation, follow-up, and analysis.
Comparison of the degree of improvement in chronic urticaria symptom scores after 4 weeks of treatment among the 4 treatment groups: (A-D) 4-fold updosing of nsAHs, combination treatment with 4 nsAHs, switching to other nsAHs, and adjunctive H2RA; and (E-H) high- and standard-dose nsAH groups. P values were calculated using generalized estimating equations.
Comparison of rescue medication use between the high- and standard-dose antihistamine groups: frequency (A) and cumulative doses (B) of rescue H1-antihistamine.