Hyperhidrosis: A targeted literature review of the disease burden

Hyperhidrosis is a chronic skin condition characterized by excessive sweating. It poses a burden on affected people, reducing their quality of life and productivity. We undertook a targeted literature review (TLR) to gather current evidence on the epidemiology as well as the human and economic burden posed on patients with hyperhidrosis. Searches were performed in Medline database (access via OVID interface) and ICHUSHI database. Articles published between January 2000 and September 2020 that analyzed at least 50 patients were included. Sixty‐four publications were identified and 38 publications covering a unique domain were selected to inform this TLR. The incidence of hyperhidrosis ranged from 0.13% in the UK to 0.28% in the USA, with a higher rate in females. The prevalence of hyperhidrosis varied from 2.8%–4.8% in the US general population to 18.40% in Chinese inpatients, while the prevalence of axillary hyperhidrosis varied from 1.4% in the US general population to 5.75% in Japanese employees/students. Due to excessive sweating, hyperhidrosis was reported to be a moderate‐to‐extreme limitation at work for the US patients, with 33.5% feeling unhappy. Patients' satisfaction was high post‐treatment. Considerable costs were related to the treatment with botulinum toxin and surgery. Hospital stays for surgery lasted from 10 h to 3 days. The percentage of patients who sought a medical consultation varied from 6.3% for Japanese patients with primary focal hyperhidrosis to 51% for the US general population with any type of hyperhidrosis. There is limited evidence of the hyperhidrosis burden, particularly among Japanese patients; however, the burden was high and limited patients' daily functioning. Future actions should include implementation of educational programs to raise awareness of the condition, conduct of larger studies, and generation of more evidence. Understanding the nature of hyperhidrosis and the burden it poses is of utmost importance.


| INTRODUC TI ON
Hyperhidrosis is a chronic skin disorder characterized by sweating in excess of what is required to maintain the regulation of normal body temperature in the entire body (generalized hyperhidrosis) or some parts of the body (localized hyperhidrosis). 1 Hyperhidrosis is classified as either primary (idiopathic) or secondary in nature. 2 Human sweat glands include eccrine and apocrine sweat glands, and the sweat that causes hyperhidrosis is secreted by the eccrine sweat glands.The etiology of primary hyperhidrosis is not well understood, but some reports attribute it to neurogenic hyperexcitation of the sympathetic circuits innervating the eccrine glands. 1 The condition brings social, psychological, professional, and emotional constraints that compromise the quality of life of affected people and their productivity.Hyperhidrosis requires a safe, long-lasting treatment.[5] The costs of hyperhidrosis are associated with trying to manage and hide the embarrassing outcomes of excessive sweating.
Common disorder-related expenses include treatment costs, dry cleaning fees, replacing clothing, shoes and accessories damaged by sweat stains and odor, over-the-counter treatments such as extra strength antiperspirants and deodorant powders, specialized clothing, pads, shields, and towels, among others.
Little is known about the epidemiology and burden of hyperhidrosis across regions to date.Therefore, the objective of the project was to gather current evidence on the burden of hyperhidrosis by conducting targeted literature reviews (TLR) on epidemiology, and the human and economic burden posed on patients with this condition.

| ME THODS
The present TLR was based on searches performed in the Ovid MEDLINE(R), in Medline database (access via OVID interface) and ICHUSHI database.We decided to include the ICHUSHI database because it gathers articles published in Japan in accordance with the goal of this study.For all TLRs, only publications released between January 2000 and September 2020 that analyzed at least 50 patients were included.TLRs on the epidemiology and human burden were focused on East Asian countries (China, Korea, Japan and Taiwan), Europe (France, Germany, Italy, Spain and the UK), and the USA.For the economic burden, no geographical restrictions were applied.The detailed inclusion criteria, including restrictions, are presented in Table 1.The search strategies, including all search terms that were used in the selected databases, are provided in Tables S1-S6.
The list of titles and abstracts was screened by an experienced analyst according to the defined inclusion and exclusion criteria to select relevant articles.For any article that met the inclusion criteria or could not be excluded based on the abstract review the full text was screened to decide on its inclusion or exclusion.
For conversion rate of the Japanese Yen (JPY) to the United States Dollars (USD) a rate of 1 USD = 130 JPY is used (as of 07 March 2023). 6

| RESULTS
A total of 64 publications were identified across the three domains.The selection of publications resulted in 38 unique publications that provided information relevant to the aim of this TLR, and out of these, 12 publications provided results for the Japanese population.

TA B L E 1
Population, intervention, comparator outcomes and study design (PICOS) criteria.

| Epidemiology of disease review
Overall, 15 publications [7][8][9][10][11][12][13][14][15][16][17][18][19][20][21] reported on epidemiological results of hyperhidrosis as described in Figure 1.The included publications varied with respect to geographical areas, clinical settings, and sample sizes, leading to a wide range of values for all outcomes.Six publications originated from the USA, five from China, and two from Germany.For Japan, only one publication reported the prevalence of hyperhidrosis 17 and no publication reported its incidence in the Japanese population.The majority of publications recruited adults; only two publications focused on adolescent patients aged 15-22 years. 19,20The proportion of males across the analyzed publications was 40%-60%.Over half of the analyzed publications provided results for over 1000 patients with six for which the number of studied patients exceeded 10 000.In 12 publications, the type of hyperhidrosis was mentioned.Prevalence estimated for focal hyperhidrosis varied widely according to the site of occurrence.In six publications, the severity of hyperhidrosis was mentioned.In two publications, all the analyzed patients had severe hyperhidrosis.UK and the USA.The incidence rate of hyperhidrosis ranged from 0.13% in the UK to 0.28% in the USA with a higher rate in females. 9e incidence rate slightly decreased over time from 0.14%* to 0.13%* between 2011 and 2013 in the UK; however, it slightly increased from 0.27%* to 0.29%* in the USA. 9Through the year 2013, the incidence rate was higher among females than males for both databases (Truven: 0.31%* vs. 0.25%* and CPRD: 0.15%* vs. 0.11%*).9a

| Prevalence
Globally, the prevalence of hyperhidrosis varied between 2.8%-4.8% in the USA 11,21  F I G U R E 1 PRISMA diagram of search results -epidemiology review.
the general population) and 16.3% in Germany (employees from around 50 companies). 16In Asian studies, the prevalence of hyperhidrosis was estimated to be 13.95% in Japan (employees/students from 20 companies or schools) in 2013 17 and 18.4% in China (patients from one hospital) in 2016. 12The most common type of hyperhidrosis with the highest number of patients was "generalized and facial hyperhidrosis" in China with a prevalence of 6.1% 12 and axillary hyperhidrosis in Japan with a prevalence of 5.75%. 17garding site and type in the general population, the prevalence of an axillary form varied from 1.4% (US general population) 21 to 5.75% (Japanese employees/students from 20 companies or schools). 17The main findings on epidemiology in the literature review are shown in Figures 2-3.Additional information on epidemiology is shown in Table S7.
Seven publications focused on patient satisfaction after treatment (most of them Japanese; yet none compared patient satisfaction among treatments), three focused on health-related quality of life, while none of the Japanese studies reported on patient reported outcomes (PROs).Nine publications were hospital-based.
Regarding patient populations, 20 studies recruited patients with a mean age of 20-40 years.The proportion of males ranged from 18.76% 31 to 100.00%. 24Most publications reported results for sample sizes of over 100 patients (19 publications), including seven studies, which enrolled over 1000 patients.The Hyperhidrosis Disease Severity Scale (HDSS) was used in eight publications, with five focusing on severe patients.

| Health-related quality of life
To evaluate health-related quality of life researchers used the HDSS questionnaire (four studies), followed by the visual analog scale (three studies), and the Dermatology Life Quality Index (DLQI) (two studies).In general, the HDSS score decreased after treatment.Apart from treatments, Hansen et al. 27  F I G U R E 3 Prevalence by disease site.

| Patient reported outcomes
The majority of the patients reported that sweating affected their daily life. 11,21A total of 16.5% of the US individuals extrapolated to the general US population who had axillary hyperhidrosis reported that they were moderately to extremely limited by their sweating at work with 33.5% of them feeling unhappy. 21

| Patients' satisfaction
All the 15 publications identified focused on patient satisfaction level after treatment and investigated changes over time.Of these, seven focused on patients in Japan.A variety of measurement instruments was used, such as the proportion of satisfaction level, the satisfaction score using a simple questionnaire, and the proportion of answers "satisfied".Two publications (from China and Spain) reported that satisfaction was usually high in the first months after the treatment or surgery; exact timing differed between publications; however, a decrease of treatment/surgery satisfaction was observed over time. 24,29A Japanese publication revealed that satisfaction after undergoing endoscopic thoracic sympathectomy (ETS) was on a comparable level after 1 month and 1 year post-treatment in 163 analyzed patients (98.7% vs. 98.3%). 36Similar to global findings, seven Japanese publications reported that treatment satisfaction was high for surgery, 23,28,31,33,[36][37][38] but no results were reported for other treatment options.
Additional information on the human burden is shown in Table S8.

| Economic burden review
Overall, 23 publications 7,8,10,11,[15][16][17]21,22,25,27,29,30,[32][33][34][35][39][40][41][42][43][44] reported on economic burden outcomes of hyperhidrosis (Figure 5). Five studies were conducted i Japan, five in the USA, and two each in China, Germany and Spain.Five Japanese publications reported results for resource-use and work impairment.No publication reporting costs of hyperhidrosis was found.One publication compared work productivity scores among dermatologic diseases; however, comparing scores was challenging as the reported scores were cited from different sources.41 The mean age in the studies ranged between 19 15 and 57.5 27  the recruited patients had severe hyperhidrosis.10,22,30,39 Five publications reported results of the HDSS scale; however, they included patients with varied backgrounds.One publication showed that 70% of people with hyperhidrosis experience severe sweating, classified as an HDSS score of 3 or 4 on at least one body area.11 The HDSS score was higher in patients undergoing botulinum toxin treatment or surgery.17,30

| Direct costs
The outcomes analyzed for direct costs included total direct cost, 29 hospitalization costs, 22,29,34 costs related to surgery, 10,29,34,43 treatment costs, 22,29,34 and costs of specialist/outpatient visits. 29,34nerally, the direct costs were higher for ETS than botulinum toxin in several countries, such as Spain (total costs: €1131.72 per one ETS F I G U R E 5 PRISMA diagram of search results -economic burden review.

F I G U R E 6
Stay after endoscopic thoracic sympathectomy.

| Resource use
For six countries, the UK, Germany, Spain, Brazil, Japan and China, most of the outcomes on hospitalization were related to hospital stay after ETS or minor invasive surgery.Our TLRs showed that a hospital stay after ETS was the longest in Japan (3 days) 42 compared to the UK (1.5 days), 15 Brazil (11.4 or 10.1 h), 43 and China (98.2% of 221 patients with severe primary palmar hyperhidrosis were discharged on the first postoperative day) (Figure 6). 10 Surgical sympathectomy was commonly used in several countries; however, in three publications a high percentage of European and US patients had iontophoresis to treat primary hyperhidrosis. 7,16,44her treatments included antiperspirants, aluminum chloride, 27 and botulinum toxin. 7The mean annual number of botulinum toxin treatments for a patient with axillary hyperhidrosis using the mean interval (5.6 months) in Ireland was 2.1. 40The proportions of patients using botulinum toxin injection were 2.6% of 313 European patients, 44 2.5% of 44 484 US patients, 7 1.1% of 746 German patients, 16 and 0.13% of 741 Japanese patients (Figure 7). 17diverse percentage of patients consulted their physician or a medical specialist on the problems brought on by hyperhidrosis.In the USA, the proportion of patients who discussed sweating with a health-care professional varied between 38.0% 21and 51%, 11 depending on the type of population.In Germany, about 30% of the patients with focal hyperhidrosis reported feeling bothered by sweating 'frequently' or 'constantly', and 55% did not consult a physician. 16In Japan, 6.3% of primary focal hyperhidrosis patients consulted a medical practitioner (Figure 8).Of 47 such patients with primary focal hyperhidrosis, 2%-6% visited a cosmetic surgeon, internal medicine specialist, psychosomatic medicine specialist, or a psychiatry/anesthesiology/surgery specialist. 17The main findings of TLR on economic burden are shown in Figures 6-8.Additional information on the economic burden is shown in Table S9.

| DISCUSS ION
This is the first comprehensive TLR study on hyperhidrosis including the epidemiology and disease burden of hyperhidrosis across regions to date.This study found limited evidence of the hyperhidrosis burden, however, it was found that the burden where it existed was high and limited patients' daily functioning.
F I G U R E 7 Botulinum toxin usage.
F I G U R E 8 Specialist consultation.
Our TLR showed that the prevalence of hyperhidrosis for the general population was the highest in Japan, 13.95% 17,45 (range: 0.21% in the UK 9 through 4.8% among the US population 11 ) (Figure 2)).The same trend was shown in recently published papers that reveal no significant change in Japan. 43This wide range in prevalence globally may suggest the role of race and genetics in hyperhidrosis, as studies have found differences in prevalence as well as the age at onset across countries and between races within a country. 5The most common types of hyperhidrosis varied by country; primary palmar hyperhidrosis in China, with the prevalence between 4.30% and 5.80% 19 and axillary hyperhidrosis in Japan with a prevalence of 5.75% 17 (Figure 3).The prevalence trends of hyperhidrosis by age group were higher in adolescents (15-19 years old; 13.02%) compared to children below 15 years old (range: 4.27%-6.53%). 17The higher prevalence of axillary hyperhidrosis in adolescents could be explained by the growing process during which intensification of sweating is usually observed, also in healthy people.
A lack of evidence on the human burden was seen in the literature, which may be due to a low level of awareness among patients.Various tools were used to evaluate the human burden, such as DLQI, PROs, and measures of patient satisfaction.The majority of the publications originated from Japan and the USA.In addition, the scope and size of Japanese publications were limited.In general, a high level of patient satisfaction after surgeries or injections was reported, but no such evidence was found for other treatments.
Furthermore, there were a few long-term observational studies of patient satisfaction levels showing different levels of satisfaction.
Isla-Tejera et al. reported that, regardless of the treatment types (ETS or botulinum toxin), the patient satisfaction level increased over a 5-year period after each treatment. 29Ambrogi et al. reported that patient satisfaction level was higher at 24 h in the botulinum toxin group compared to the surgery group.At 6 months, the patient satisfaction level was higher in the surgery group compared to the botulinum toxin group. 21Heterogeneity of evaluation tools and existing gaps in the current knowledge regarding hyperhidrosis suggest that the implementation of educational programs for physicians, medical specialists, and patients to raise awareness of the disorder may be important.Comprehensive understanding of the human burden may be a potential area for further investigation in Japan as evidence from Japan remains limited regarding the size and scope of outcomes studied.
In terms of economic burden, most publications reported direct cost and resource use, mainly on hospitalizations.For Japan especially, data on the economic burden were limited with no publication found on treatment costs.However, recently, a cost-of-illness study for axillary hyperhidrosis was published and reported that the annual direct medical costs per axillary hyperhidrosis patient were ¥75 000-93 000 (US$576.9-715.4). 46This was less than in other countries, perhaps due to the more frequent inclusion of less severe patients in Japanese studies and the differences in the health-care system.Our TLR shows that the economic burden is still not well understood or described in the literature, especially the indirect cost of hyperhidrosis.Nevertheless, three publications 35,41,43 reported on productivity loss and the number of days before returning to work, which suggested that hyperhidrosis may have a negative social impact.Despite the chronicity of the condition, only one cost study was found, showing that the treatment cost decreased over the years. 29e proportion of patients who consulted a physician or medical specialist about their hyperhidrosis ranged from 38.0% for the US general population 21 to 45% for focal hyperhidrosis in patients from around 50 companies in Germany. 16Only 6.3% of surveyed patients (employees/students from 20 companies or schools) had a medical consultation in Japan. 17The same trend was shown in a recently published paper, which shows that 9.5% of patients with hyperhidrosis visited medical institutions. 47

ACK N OWLED G M ENTS
We express our gratitude to Yoshie Onishi, of Creativ-Ceutical, for her contribution to preparation of the manuscript.Special thanks to Malgorzata Biernikiewicz of Creativ-Ceutical for editing the manuscript.Their assistance was funded by Maruho Co. Ltd.Maruho Co.
Ltd sponsored the study, contributed to the design, participated in the analysis and interpretation of data as well as writing, reviewing, and approval of the final version.No honoraria or payments were made for authorship.

CO N FLI C T O F I NTE R E S T S TATE M E NT
This study was funded by Maruho Co. Ltd.Yuichiro Oshima and Tomoko Fujimoto received a consultancy fee from Maruho Co. Ltd.
Akihiko Ikoma and Junko Fukui are employees of Maruho Co. Ltd.
Mariko Nomoto is an employee of Creativ-Ceutical and received a grant from Maruho Co. Ltd during the conduct of the study.

R E FE R E N C E S
(nationally representative samples from a Asterisks indicate the values were approximate, based on the source figure reading software (Grafula3 v2.10).

32 F I G U R E 2
reported that the burden of sweating worsened during the summer compared to other seasons.A Japanese publication revealed that treatment with botulinum toxin reduced severity of axillary hyperhidrosis symptoms, measured by the mean HDSS score from 3.51 at the baseline (n = 395) to 2.26 at the end of observation period (n = 395).Overall prevalence of hyperhidrosis.
years.Most of 15 publications recruited patients over the age of 27.Men were a minority in 13 out of the 15 publications.Although the analyzed groups of hyperhidrosis patients were rather small, most of the publications provided results per patient.In four publications, all F I G U R E 4 PRISMA diagram of search results -human burden review.

3. 3 . 3 |
Productivity lossTime to return to work varied by treatment methods.The mean time to return to work of patients who underwent ultrasonic scalpel ETS and monopolar cautery ETS was 4.8 days and 5.7 days respectively in 140 Brazilian patients with palmar axillary, craniofacial hyperhidrosis, and rubor facial.43

(Figure 8 )
These lower rates inJapan may be due to a lack of disease awareness among patients, physicians, and society as well as cultural reasons, including psychological factors such as embarrassment experienced by patients and the great attention paid in Japan to good physical appearance.The overall results of our study indicate that hyperhidrosis brings burdens, physically, psychologically, and economically, worldwide and in Japan.However, new topical anticholinergics were launched in the past few years in the USA and in Japan, and it is expected that the treatment landscape would improve by increasing treatment options for physicians and patients.This recent introduction of new treatments may drive the change through increased awareness of hyperhidrosis among physicians and patients and development of new treatment policies and guidelines.Under this changed landscape, hyperhidrosis may become one of the focused research areas in the field of dermatology and larger, more comprehensive studies using more standardized definitions may be expected in the future.These may contribute to the accumulation of evidence needed for a better understanding of hyperhidrosis.Furthermore, a recent study on the cost-effectiveness of the new topical anticholinergics from the US suggested a positive economic impact.48This study is not without limitations.Due to the heterogeneity of populations evaluated in the included publications (e.g., geographical areas and sample sizes) descriptions and comparisons of defined outcomes by studies across publications were difficult.This heterogeneity may lead to potential biases, posing challenges to the generalizability of the findings.Furthermore, this study covers literature published between January 2000 and September 2020, therefore research needs to be updated for trends beyond that date.Further literature reviews after the uptake of new treatments, such as topical anticholinergic leading to the changes in perception of hyperhidrosis, are needed.In addition, disease surveillance of hyperhidrosis is required to capture the current epidemiology of the disorder.In conclusion, evidence on the epidemiological, human, and economic burden of hyperhidrosis is limited, particularly among Japanese patients and patients with axillary hyperhidrosis.Despite limited data, available evidence suggests that hyperhidrosis places physical, psychological, and economic burdens on the daily lives of individual patients.The introduction of new treatments is expected to improve the medical environment of hyperhidrosis and reduce the burden on patients.Future actions should include implementation of educational programs for physicians, medical specialists, and patients to raise awareness of the condition; the conduct of further studies with larger scope and bigger patient populations; and the generation of more evidence for Japan.Addressing the gaps in knowledge revealed in this study can help understand the nature of hyperhidrosis and the extent of the burden of this condition.