Demographics and CU clinical characteristics
Sixty-one adult patients with CU were evaluated, 73.8% (n=45) were female and 26.2% (n=16) male. The median age of patients was 44.5 ± 14.9 years, ranging from 18 to 84 years old. Most patients (78.7%) had initiated CU symptoms less than 1 year before enrollment (Table 1).
Regarding the characterization of the CU type, 55.7% (n=34) were diagnosed with CSU and 44.3% (n=27) with CSU associated with CIndU as a comorbidity. The ClndU subtypes diagnosed in our population are shown in table 2 (70.4% of patients were afflicted by more than on type of ClndU and all had associated spontaneous urticaria). Females accounted for 88.9% (n=24/27) of ClndU patients, while only 61.8% of the CSU (n=21 /34) were females (p=0.021, Chi-Square Tests).
Thirty-four patients (55.7%) had at least one episode of angioedema within the last year. The presence of angioedema did not significantly associate with sex, age, recent onset of CU or the subtype of CU.
Comorbidities
The frequency of comorbid atopic diseases was: asthma in 21.3% (n=13), rhinitis in 29.5% (n=18) and the combination of the two diseases in 32.8% (n=20). Medically‐confirmed psychiatric disorders (depression and / or anxiety disorder) were present in 78.7% (n=48). Other comorbidities, such as arterial hypertension, type 2 diabetes and obesity were present in 31.2% (n=19).
Table 1. Demographics and medical history of the patients included. Please note that some patients present several comorbidities.
Variable
|
Population cohort (n = 61)
|
Age
|
Median, years (min, max)
|
44.5 (18, 84)
|
Gender
|
Women
|
73.8% (n=45)
|
Years since urticaria diagnosis
|
|
<1 year
|
78.7% (n=48)
|
2-5 years
|
9.8% (n=6)
|
6-10 years
|
8.2% (n=5)
|
>10 years
|
3.2% (n=2)
|
Comorbidities
|
57.4% (n=31)
|
Allergic diseases
|
Asthma and Rhinitis
|
32.8% (n=20)
|
Rhinitis
|
29.5% (n=18)
|
Asthma
|
21.3% (n=13)
|
Food allergy
|
3.3% (n=2)
|
Atopic dermatitis
|
1.64% (n=1)
|
|
|
Autoimmune diseases
|
|
Autoimmune thyroid disease
|
11.5% (n=7)
|
Psoriatic arthritis
|
1.64% (n=1)
|
Cardiometabolic
|
Arterial hypertension
|
19.7% (n=12)
|
Diabetes
|
6.6% (n=4)
|
Obesity
|
4.9% (n=3)
|
History of acute myocardial infarction
|
1.64% (n=1)
|
Psychiatric disease
|
Depression and/or anxiety disorder
|
78.7% (n=48)
|
|
|
Malignant diseases
|
|
Follicular thyroid tumor
|
1.64% (n=1)
|
Table 2. ClndU subtypes in the study population. Please note that some patients present with several CIndU subtypes
ClndU subtypes
|
Number of patients
|
Delayed pressure urticaria
|
19.7% (n=12)
|
Cholinergic urticaria
|
14.8% (n=9)
|
Heat urticaria
|
14.8% (n=9)
|
Symptomatic dermographism
|
13.1% (n=8)
|
Cold urticaria
|
4.9% (n=3)
|
Contact urticaria
|
4.9% (n=3)
|
Solar urticaria
|
1.6% (n=1)
|
Aquagenic urticaria
|
1.6% (n=1)
|
Diagnostic work-up
Complementary diagnostic tests were performed in cases in which the clinical history suggests an underlying etiology, according to the local follow-up protocols, namely for patients with more severe presentation (UAS7 ≥28 and/or UCT <12) or with longer evolution (>1 year).
Complementary tests performed for further classifying CU were complete blood count (CBC), erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP), all performed in 68.9% (n=42), and the least frequent tests were skin biopsy, requested for only 6 patients. All patients evaluated had a CBC within the reference values; CRP was high in six patients (6/42 = 14.3%) and half of these also had ANAs+. In patients with high CRP results, infectious causes such as HSV, HBV, CMV, EBV and HIV were excluded. Regarding ESR testing (n=42), none of the patients presented abnormal values (1-20 mm / h).
Evidence for autoimmunity markers (positive anti-thyroid peroxidase antibodies, anti-nuclear antibodies or AutoST) was found in 45.2% (n=19) of 42 tested patients. Anti-nuclear antibody (ANAs) assay was positive in one third (n=14)of 42 tested patients. The “dense fine speckled” was the most frequent (n=10), followed by the “nucleolar pattern” (n=4). Routine measurement of thyroid stimulating hormone (TSH) has not been approved by international guidelines since 2018(2). Among patients who had ANAs+, 21.4% (n=3/14) had a diagnosis of autoimmune thyroid disease (ATID). The remaining 4 cases of AITD were ANAs-, corresponding to a total of seven patients (7/42 = 16.7%).
The AutoST was performed in 9.8% (n=8) patients with suspected diagnosis of autoimmune urticaria. Only one patient (out of 8) had a positive AutoST. This patient had been diagnosed with CU less than 1 year before evaluation and had a severe presentation of the disease, only partially controlled with the four antihistamines/day and omalizumab, and with frequent job absenteeism due to CU. The patient was also ANAs+ but negative for autoimmune thyroid antibodies.
Skin biopsy was requested in patients with uncommon presentations, namely in painful lesions. Skin biopsy was performed in 9.8% (n=6) of the patients and five presented interstitial edema with a perivascular mixed infiltrate (lymphocytes, eosinophils, and in few neutrophils /basophils).
One patient presented vasculitic signs and hypocomplementemic urticarial vasculitis (McDuffie syndrome) was diagnosed. This was a 44-year-old female patient who presented urticaria with angioedema refractory to 4id antihistamine treatment, with about 1 year of evolution. She was submitted to a first skin biopsy due to painfull lesions, but no findings of vasculitis were found. Six months later, she started to present Raynaud phenomenon and developed echymotic papules. In this context, the skin biopsy was repeated on suspicion of vasculitis and the diagnosis of McDuffie syndrome was made. Histology showed the presence of slight angiocentric lymphohistiocytic infiltrate with the presence of some dispersed polymorphonuclear cells and also mild leukocytoclasia. Currently, she is under prednisolone 20mg/day plus bilastine 20mg/day with symptom control.
Urticaria with a predominance of neutrophils on histology was not found in any patient.
Treatment
All patients were on first-line therapy with non-sedating H1 antihistamines at the time of evaluation, with the majority of the patients receiving a twice-a-day regimen (52.4%, n = 32, Table 3). Among those treated with omalizumab (n = 4), four had CSU, one of them with autoimmune urticarial confirmed by AutoST+, and one had several subtypes of ClndU, namely cholinergic urticaria, pressure urticaria and symptomatic dermographism. Atopy was present in all patients receiving montelukast therapy as additional therapy, resulting in an improvement of CU control with its introduction, resulting in a reduction in the number of daily antihistamines to 1id in all cases. One patient was treated with ciclosporin after therapeutic failure with omalizumab. This was a 45-year-old female patient, with obesity and arterial hypertension, with CSU associated with angioedema diagnosis <1 year and presenting poorly controlled CU and angioedema despite medication with cetirizine four times a day (40mg) and showing no clinical worsening of arterial hypertension at the time of data collection.
Three patients were evaluated during acute exacerbations and were under treatment with systemic corticosteroid therapy as additional therapy. The other patient who was medicated with systemic corticosteroid therapy was referred to the case of McDuffie syndrome. In association, this patient was medicated with one H1-AH per day.
Table 3. Active treatment at enrolment in the study population.
Variable
|
Population cohort (n = 61)
|
Treatment
|
|
Non-sedative H1-antihistamines
|
100% (n=61)
|
Number of daily doses
|
|
4
|
14.8% (n=9)
|
3
|
13.1% (n=8)
|
2
|
52.4% (n=32)
|
1
|
19.7% (n=12)
|
Montelukast
|
|
Yes
|
13.1% (n=8)
|
Omalizumab
|
|
Yes
|
6.6% (n=4)
|
Systemic corticotherapy
|
|
Yes
|
6.6% (n=4)
|
Ciclosporine
|
|
Yes
|
1.6% (n=1)
|
Clinical exacerbations and disease control
Disease status was evaluated using two outcomes: significant exacerbations and activity/disease control scores (UAS7 and UCT). Significant exacerbations of CU were defined by the need of unscheduled medical consultations, emergency room, hospitalization or job absenteeism. Forty -six patients (75.4%) had at least one significant exacerbation during the previous year. The median number of visits to the Emergency Department (ED) was one visit/patient/year, with the majority of patients (45.9%, n=28) presenting with one or two ED episodes in one year, and a maximum value of four visits in one year. Hospitalizations due to CU exacerbation occurred in 8.2% (n=5) of the patients, and four of these patients had both CU and angioedema presentation for less than 1 year. Unplanned consultations were needed in about half of the population and job absenteeism occurred in 14.8% (n=9) of patients, with a maximum of 90 days and a minimum of 1 day (Table 4).
Table 4. CU exacerbations (ED episodes, hospitalizations, unplanned consultations and job absenteeism)
Variable
|
Population cohort (n = 61)
|
CU exacerbations
|
75.4% (n=46)
|
Visits to the Emergency Department
|
|
>3
|
9.8% (n=6)
|
1-2
|
45.9% (n=28)
|
0
|
44.3% (n=27)
|
Hospitalizations
|
|
2
|
3.3% (n=2)
|
1
|
4.9% (n=3)
|
0
|
91.8% (n=56)
|
Unplanned consultations
|
|
>7
|
4.9% (n=3)
|
5-7
|
8.2% (n=5)
|
3-4
|
19.7% (n=12)
|
1-2
|
19.7% (n=12)
|
0
|
47.5% (n=29=)
|
Job absenteeism
|
|
Yes
|
14.8% (n=9)
|
The number of exacerbations correlated with higher UAS7 symptom scores (p=0.006, Spearman correlation). In our sample, patients with ClndU had worst disease control scores (UAS7 and UCT questionnaires) when compared to patients with CSU only (p=0.022, Mann-Whitney test). However, ClndU patients had fewer exacerbations requiring medical observation or hospitalization (p=0.015, Mann-Whitney test).
A high number of antihistamines, use of corticosteroid therapy and/or ciclosporin for disease control correlated with higher UAS7 scores (p = 0.006, Spearman correlation) but no significant correlation was observed with the UCT score. The presence of angioedema associated with a higher number of exacerbations (p=0.022, Mann-Whitney test) but with no differences concerning disease control (UAS7 and UCT), or the number of antihistamines used. Atopy (allergic asthma, allergic rhinitis, food allergy and atopic dermatitis) and autoimmunity (positive antithyroid peroxidase antibodies, ANAs and / or AutoST) did not significantly associate with the symptom scores or exacerbations. No other statistically significant associations were observed in relation to other variables, namely, complementary diagnostic tests or the presence of comorbidities.