Verbal expressions describing itch quality in atopic dermatitis and urticaria: an online questionnaire survey in Japan

Methods: We conducted an online questionnaire survey describing itch experiences in June 2021. Participants were Japanese patients who had


Introduction
Itch is the most burdensome symptom in all age groups with atopic dermatitis (AD).It is associated with the development of sleep disorders, psychiatric disorders, and impaired quality of life in patients [1,2].The perception of itch is very personal and subjective and varies not only in intensity but also in its triggers, the time of day and season, the body area involved, and treatment methods, depending on the patient.Itch is sometimes severe despite mild skin symptoms in AD [3,4].Therefore, it is important to focus on itch as well as skin symptoms for the treatment of AD.
The nature of itch sensation may also vary depending on the individual patient and the disease.If we know how patients perceive and express their feeling of itch using words, we can assess the quality of itch.The visual analog scale and numerical rating scale (NRS) commonly used to evaluate itch can only assess the intensity of itch felt by patients.The classification of itch based on differences in itch quality may help choose and develop more appropriate treatments.However, few studies have examined the quality of itch [4][5][6][7].
This study was therefore conducted an online questionnaire to investigate the quality of itch using verbal expressions describing itch felt by patients.The participants were patients with AD and were compared with those with urticaria.We, here, described their frequency of use and associations with severity, site, season, time of day, and treatment response for the expressions describing itch and compared them between the diseases.

Questionnaire and participants
An advance survey was conducted to collect Japanese expressions commonly used to describe the itch sensation by patients with AD or urticaria as answers to an open-ended question.After excluding emotional words such as "troublesome" or "unbearable" from the collected expressions,  S1), discussed the candidate expressions and determined a list of 12 terms describing itch that responders could select in the questionnaire (Table 1).
In June 2021, we conducted an online questionnaire survey through Macromill Carenet, Inc., an online survey company (Tokyo, Japan).This study required no ethics approval because of its use of completely anonymized data of the study participants, with no patient contact involvement.A questionnaire, written in Japanese, was distributed to patients with AD or urticaria registered on a panel  The screening questionnaire stated the purposes of the survey and asked patients who had visited hospitals for AD or urticaria in the last 6 months to answer questions.Those who gave voluntary informed consent were included in the analysis.All data were anonymized by Macromill Carenet and supplied to Maruho Co., Ltd.(Osaka, Japan) for the analysis.
The questionnaire included the following items: [1] patient information, including sex, age, disease duration, NRS score for the most intense itch for the last week, and prescribed therapeutic drugs; [2] regarding expressions describing intense itch that patients experienced at least once and could not help scratching, all expressions describing experienced itch (multiple choice) and one expression that best described their itch on the list of 12 terms (single choice, hereafter referred to as the most suitable expression); [3] the body area, season, and time of day at which they often experienced intense itch and the most suitable expression describing the itch; and [4] the most suitable expression describing the itch sensation that made them happiest if improved (single choice), [5] all expressions describing the itch improved by therapeutics (multiple choice), and [6] all expressions (multiple choice) and the most suitable expression (single choice) describing the itch felt even after the skin symptoms subsided.

Statistical analysis
The proportion of patients who had experienced the situation in question and the proportion of the most suitable expression describing the itch that the patients selected were calculated.In the calculations, the denominators excluded patients who were ineligible for each question.The proportions were compared between the AD and urticaria groups using Fisher's exact test.Because these comparisons were exploratory, no correction was used to adjust for multiple testing.All statistical analyses were performed using IBM SPSS Statistics 28.0 (IBM Corp, Armonk, NY, United States).

Background of the respondents with AD or urticaria
Responses from 295 patients with AD and 290 patients with urticaria were included in the AD and urticaria groups, respectively.The patients' background characteristics are shown in Table 2.More women were included in the urticaria group than in the AD group.The most common severity grade for the last week using the NRS for the most intense itch was "moderate" in the AD group, whereas it was "severe" in the urticaria group.The disease duration of the AD group ranged from 6 months to >30 years.Among the patients in the AD and urticaria groups, 288 (97.6%) and 277 (95.5%), respectively, received prescribed drugs at present.

Expressions describing intense itch that patients cannot help scratching
The proportion of all the expressions describing intense itch that patients could not help scratching were shown in Figure 1A; Supplementary Table S2.Common terms were "muzumuzu" (creepy-crawly itch, a bit like tickling) (63%), "painful itch" (48%), and "chikuchiku" (prickly itch, like wearing a sweater right on skin) (33%) in the AD group.Many patients with AD experienced itch that was described by these terms compared with urticaria patients.In the urticaria group, common terms describing intense itch were "muzumuzu" (53%), "itch like mosquito bites" (41%), and "painful itch" (37%).The most suitable expression of intense itch was "muzumuzu" in both groups (AD, 29% vs. urticaria, 25%) (Figure 1B; Supplementary Table S2).However, the second and third expressions were different between the two groups.These were "painful itch" (21%) and "hard to describe itch" (14%) in the AD group but "itch like mosquito bites" (23%) and "painful itch" (17%) in the urticaria group.Comparing AD and urticaria, the proportions of patients who felt "itch like mosquito bites" and "burning itch" were significantly higher for urticaria than for AD, whereas "chikuchiku" was significantly higher for AD (10%) than for urticaria (4%).
The mean number of expressions describing intense itch selected by AD patients was 2.1 for children aged 7-15 years (n = 54) and 3.2 for those ≥16 years (n = 241).Therefore, children aged 7-15 years experienced itch at an overall lower proportion of patients than those aged ≥16 years in the AD group (Supplementary Figure S1A).In contrast, the mean number of expressions selected by patients with urticaria was 2.5 for those aged 7-15 years (n = 51) and 2.7 for those ≥16 years (n = 239), suggesting similar number regardless of age (Supplementary Figure S1B).
The mean number of expressions describing intense itch increased with severity for the last week as per grading using the NRS.The mean numbers for mild, moderate, and severe grades were 2.3, 3.0, and 3.7, respectively, in the AD group and 2.2, 2.7, and 3.2, respectively, in the urticaria group.Overall, the most suitable expressions describing intense itch were similar regardless of NRS severity (Supplementary Figure S2).

Comparisons with body area, season, and time of day in which patients often experienced intense itch
The most predominant area, season, and time of day in which patients with AD and urticaria most frequently feel an intense itch were almost similar between the AD and urticaria groups (Supplementary Figure S3).However, the most suitable expression varied with body area, season, and time of day in AD.Of the most suitable expressions for frequent itch areas, "painful itch" for hands (31%) and legs/knees (35%) and "muzumuzu" for arms/elbows (30%) were selected more in the AD group.In the urticaria group, "itch like mosquito bites" and "muzumuzu" were selected more commonly for the above most frequent areas with intense itch (Supplementary Table S3).
Among the most suitable expressions describing itch for season in the AD group, "muzumuzu" was most common in spring, autumn, and all seasons, and "painful itch" was most common in summer and winter.In the urticaria group, "muzumuzu" was most common in spring and summer, "itch like mosquito bites" in winter and all seasons, and "chikuchiku" in autumn (Supplementary Table S4).
Of the most suitable expressions describing itch in the evening and at bedtime, "muzumuzu" was selected most frequently for both AD (32%) and urticaria (34%).Also at night, "muzumuzu" was the most frequent in the AD group (37%) (Supplementary Table S5).

Expressions describing itch in association with treatment
Expressions describing itch that would make patients happiest if improved were "painful itch" (27%) and "muzumuzu" (23%) in AD patients and "muzumuzu" (23%), "itch like mosquito bites" (22%), and "painful itch" (19%) in urticaria patients (Figure 2; Supplementary Table S6).The proportion of AD patients who selected "painful itch" was significantly higher than that of urticaria patients.The proportion of urticaria patients who selected "itch like mosquito bites" was significantly higher than that of AD patients.

Discussion
Japanese is a language that extensively uses mimetic words (ideophones), which are also often used to express itch sensations [8]; for example, "muzumuzu," "chikuchiku," and "piripiri."Although it is difficult to correctly translate them into English, we have shown English explanations in Table 1.
Patients with AD and urticaria used various expressions describing the itch sensations they experienced, and the itch sensations felt by patients were not homogeneous or uniform.The primary terms for itch sensations were "muzumuzu" and "painful" in AD patients, and "muzumuzu," "itch like mosquito bites," and "painful itch" in urticaria patients.In this study, we found significant differences in the proportion of AD and urticaria patients using the expressions "muzumuzu," "painful itch," "chikuchiku," "tickling itch" (AD > urticaria), and "itch like mosquito bites" (AD < urticaria).Thus, the expressions describing itch sensations selected in AD and urticaria patients are different, raising the possibility that differences in itch quality are classified by the terminology used to describe it.
Huet et al. indicated that in a web study of 170 patients with AD aged ≥14 years, burning itch and stinging (about 60% each) were the most common symptoms associated with pruritis, suggesting a neuropathic component [6].Similarly, our present study shows that almost half of the AD patients experienced "painful itch," which was significantly more frequent than urticaria patients.Furthermore, this type of itch sensation would make patients happiest if improved.Our results are consistent with recent studies demonstrating that pain in AD patients is a major component of the disease burden [9].
The most frequently selected "muzumuzu" itch feels like crawling skin.Huet et al. reported that crawling skin was a minor type in itch, ranking fifth out of eight major types of itch in French patients with AD [6].However, previous Japanese studies on the quality of the itch experienced in AD [10] and urticaria [11] revealed that patients with these conditions describe the itch using more expressions related to crawling skin than expressions related to painful itch such as "chikuchiku," "piripiri," "burning," and "stinging."This finding is consistent with our results.Yosipovitch et al. also reported that crawling skin was most common in patients with AD of Chinese descent living in Singapore, followed by tickling, which was more common than burning itch or stinging [5].Since these reports and our study did not assess the same itch descriptions, direct comparisons are difficult.However, itch sensations expressed with "muzumuzu" itch and crawling skin may be more specific to Asians.
The body area where AD patients most often experienced intense itch was the hands.In AD, hand eczema is intractable and may trigger severe itch, and consideration of this data is important for therapeutic intervention.Regarding the season and the time of day, half of the patients with AD and urticaria felt intense itch in the evening, at bedtime, and at night.In AD patients, "muzumuzu" was often felt on the arms, elbows, hands, head, neck, and back, in spring and autumn, in the evening, at bedtime, and at night.However, a "painful itch" was often felt on the hands, legs, and knees during the day in summer and winter.
The type of itch that would make patients happiest if improved was different between the diseases."Painful itch" and "muzumuzu" accounted for about 30% and 20%, respectively, of AD patients.In contrast, "muzumuzu," "itch like mosquito bites," and "painful itch" were each reported by 20% of urticaria patients.Thus, the types of itch that patients hope to improve varied from patient to patient.Therefore, treatment satisfaction would be improved by paying attention to the kind of itch each patient hopes to improve.
Notably, 55% of patients with AD and 41% of patients with urticaria answered that they sometimes felt itch even after skin symptoms had subsided.The higher the itch severity, the higher the percentage of patients who felt itch.In both diseases, "muzumuzu" was the most suitable expression for describing the itch felt even after disappearance of skin symptoms.Whether differences in the pruritogen affect the quality of the itch sensation is an interesting question, but direct evidence remains lacking.Hence, the type (s) of pruritogens that induce the "muzumuzu" feeling remain unclear.We found that "muzumuzu" was predominantly selected by patients with both histaminergic (urticaria) and nonhistaminergic (atopic dermatitis) diseases, indicating that multiple factors can induce this sensation.Thus, "muzumuzu" is a type of itch independent of skin inflammation and might be associated with neural sensitization [12].Peripheral sensitization is caused by cytokines or the deactivation of an inhibitory system for mechanical itch [13][14][15][16], and central sensitization is mediated by spinal glial cells activation, neuroinflammation, and cytokine production to maintain central sensitization, leading to chronic itch [17].As remnant itch can lead to a relapse of skin rash due to scratching, treatment for itch is important after skin symptoms subside.Because "muzumuzu" tends to persist, it would be helpful to continue treatment in patients who continue to have this feeling.Nevertheless, while "muzumuzu" was the most predominantly selected expression among both patient groups, the other expressions selected differed between respondents with these pruritic skin diseases."Painful itch" and "chikuchiku" were prominent choices in the AD group.Conversely, "itch like mosquito bites" was deemed more characteristic of urticaria, indicating that this particular sensation may be specific to histaminergic itch.Furthermore, the second most predominant itch descriptions felt after skin symptoms had subsided also differed between these pruritic skin diseases.Therefore, we believe that different pruritogens affect the quality of the itch sensation, as reflected by the expressions selected to describe it.
The emergence of many new drugs for AD has made it possible to treat itch more effectively.To select treatment for each patient, it may be worth focusing on itch expressions patients use and the treatment responsiveness of these patients.Establishing effective treatments in the future for each itch type will enable treatments more suitable for each patient.
The major limitation of this study was the use of an online questionnaire survey that could not accurately capture the diagnosis and disease severity or contrast expressions describing itch with feelings related to skin lesions.We collected the itch terms that patients have experienced to try to gain a comprehensive understanding.However, the terms to describe itch in pediatric patients aged ≤15 years were fewer than in the other age groups.This may be because describing their sensations is difficult, in addition to having fewer itch experiences.
In conclusion, while various itch characterizations have been made around the world, this online questionnaire survey revealed the characteristics of itch in Japanese patients with AD or urticaria.Although a further study is needed on the simultaneous evaluation of symptoms and itch expression, on the evaluation of treatment responsiveness based on itch expression, these findings may lead to a better understanding of itch symptoms and improved treatment outcomes.

of
>10 million people across Japan assembled by Macromill and recruited for the study.The target sample size was set at 270 for each disease, although no statistical hypotheses were proposed.Furthermore, the sample consisted of 50 patients in each age group (7-15, 16-25, 26-35, 36-45, and 46-64 years old) and 20 patients aged ≥65 because of low prevalence.Patients aged 7-15 years were first-born children, and their responses were provided by their parents.

FIGURE 2
FIGURE 2Expressions describing the itch that would make patients happiest if improved (single choice).Data are presented as the proportion of patients.AD, atopic dermatitis.

FIGURE 3
FIGURE 3Proportion of patients with an itch symptom even after skin symptoms subsided.The overall proportion and the proportion of patients by itch severity for the last week are shown.AD, atopic dermatitis.

FIGURE 4
FIGURE 4Expressions describing itch felt after skin symptoms subsided.(A) Proportion of all the expressions describing experienced itch (multiple choice).(B) Proportion of one expression that was the most suitable of 12 terms (single choice).AD, atopic dermatitis.

TABLE 1
Twelve terms used to describe itch sensations.