The management of Chronic Hand Eczema: A retrospective patient record review

Chronic Hand Eczema (CHE) is a heterogeneous fluctuating inflammatory disease that represents a significant burden. Effective treatment options for moderate to severe CHE are limited.


| INTRODUCTION
Hand eczema is a heterogenous, fluctuating chronic inflammatory skin disease of the hands and wrists, characterized by symptoms of pain and itch. 1 Inflammatory signs and symptoms are most frequently associated with a flare-up, while dry skin, hyperkeratosis and flaking can persist between flares. 2 Hand eczema has a multifactorial pathogenesis, with more than one aetiological or clinical subtype often involved. 3,4However, contact dermatitis is the most frequent aetiology. 4nd eczema has an estimated one-year prevalence of 9% and lifetime prevalence of 15% in the general population. 5It is a longlasting disease, with a median duration of 11-16 years. 5Hand eczema that lasts ≥3 months or that relapses twice or more in a year is considered chronic. 4The majority of patients with Chronic Hand Eczema (CHE) have moderate to severe disease. 6Risk factors for CHE include a history of atopic dermatitis and work exposure, with high incidences reported among wet-work occupations including hairdressers, nurses, and metal workers. 4,7HE can negatively impact all aspects of daily living, while the visibility of the hands can contribute to a considerable psychological burden. 8Pruritis and pain may result in impaired sleep and avoidance of social and physical activities, while symptom-related self-consciousness may lead to poor self-esteem, social anxiety and isolation. 1,9Over half of patients with severe CHE and an inadequate response to topical corticosteroids report anxiety and/or depression. 10The impairment in healthrelated quality of life for patients with moderate to severe CHE is similar to that in patients with atopic dermatitis or psoriasis. 11CHE also represents a significant socioeconomic burden, with a recent systematic review reporting that up to 57% of patients with CHE took sick leave and up to 25% reported leaving or changing their job due to CHE. 12 CHE is challenging to treat due to its relapsing nature, characterized by recurring flares, and the need for long-term management.
Patients with moderate to severe CHE who do not respond adequately to topical therapies (i.e., corticosteroids, calcineurin inhibitors) have limited treatment options.Guidelines recommend phototherapy and various systemic therapies but evidence for their effectiveness is limited. 4,13Alitretinoin is the only systemic therapy specifically approved for treatment of CHE; however, it is only indicated in patients with severe disease, while several contraindications and lack of availability in some countries further limit its adoption.
There is a dearth of knowledge on how patients with moderate to severe CHE are treated so the objective of this multinational retrospective patient record market research review was to elicit information on how CHE is managed in daily clinical practice.

| METHODS
A retrospective review of patient records was conducted by physicians to assess the demographic, clinical and treatment characteristics of adult patients (aged ≥18 years) with CHE by physicians in Belgium, Canada, France, Germany, Italy, the Netherlands, and the UK.
Participating physicians were primarily dermatologists but also included allergists in France and non-dermatologist physicians with a special interest in dermatology in the UK.Physicians were identified from existing country-specific panels provided by the healthcare market research firm M3 Global Research, London, UK and were anonymised to the sponsor.A pre-defined quota of physicians was decided upon prior to starting recruitment based on the numbers available in the panel, with a plan to recruit a pre-defined number from each medical speciality and country.Once this quota was met for each medical speciality in each country, no further physicians were approached.
To be eligible to participate in the survey, physicians had to have been in clinical practice in their specialty for 3-35 years and to have spent a minimum of 70% of their work time in clinical practice.Dermatologists also had to make treatment decisions for either ≥15 (France, Germany, Italy and the UK), ≥10 (Canada and the Netherlands) or ≥6 (Belgium) patients with moderate to severe CHE in a typical 3-month period.The use of different patient number thresholds was a practical consideration driven by differences in physician workload between countries and the need to recruit a quantitative sample in each country in a timely manner while also recruiting physicians with as much experience of managing these patients as possible.Non-dermatologist physicians with a special interest or allergists had to see ≥10 patients with CHE in a typical 3-month period.
Each participating physician was requested to review patient records for the three patients with CHE that they had seen most recently.Patients had to be diagnosed with moderate to severe CHE at the time of their last treatment initiation, based on individual physician assessment rather than any standardized definition, and be receiving topical or systemic prescription treatment for their CHE.Information on patient demographics (age, gender), clinical characteristics (disease duration, signs and symptoms) and current treatment (including time since initiation) were reported by physicians via an online survey questionnaire.Physicians were requested not to provide any personal identifiable information for patients during the survey to ensure anonymity.
The study was conducted by an independent market research agency (Lumanity, London, UK) in accordance with European Pharmaceutical Market Research Association (EphMRA) and European Society for Opinion and Marketing Research (ESOMAR) guidelines, as well as any local data protection laws.Given that this study was a physician survey of retrospective and anonymised patient data intended for market research purposes, no ethical approval or informed patient consent was required.All participating physicians had previously opted in to receive requests to participate in surveys, provided written consent to participate in this survey, and were informed and consented to the publication of aggregated data in a scientific journal.
Physicians were renumerated with a fixed payment fee for their participation in the survey.

| Stepwise hierarchical analysis
In order to give a simple overview, treatment was also analysed using a stepwise hierarchical approach to indicate the line of treatment used per patient.In this, only one treatment was reported per patient, which was the highest ranked treatment in the hierarchy (with the highest rank assigned to biologics and lowest rank assigned to topical calcineurin inhibitors).
A total of 264 physicians participated in the survey between 22 November 2021 and 1 February 2022.A further 443 potential participants completed the screening questionnaire but did not meet the criteria to participate and 103 respondents were eligible but were not asked to complete the questionnaire as the target quota had already been reached for the country and specialty.The majority of participating physicians were dermatologists (88.6%, n = 234); 3.0% (n = 8) were allergists and 8.3% (n = 22) were physicians with special interest.
These physicians reviewed the records of 792 patients with CHE.
Hyperkeratosis was present on the hands of 34.1% of patients.Atopic dermatitis was the most frequently reported aetiology (39.9%), with occupational irritant contact dermatitis reported as aetiology in 26.4% of participants.Mean time since initiation of current treatment was 16.7 ± 15.8 months (median 12 range 1-68).Over half of patients had eczema on their hands only (56.4%, n = 447); of the 43.6% (n = 345) who also had signs or symptoms on their feet and/or elsewhere on their body, these were most severe on hands in 51.6% (n = 178).Patients with signs or symptoms on hands and elsewhere were more likely to have an atopic dermatitis aetiology and a longer time since diagnosis, while patients with only their hands affected were more likely to have occupational irritant contact dermatitis and to have been diagnosed in the previous 12 months.Skin clearance on hands between flares was achieved by 59.7% of patients.Excluding the 174 patients continuously in flare, the mean (±SD) number of flares experienced by the other 618 patients in a typical 12-month period was 3.2 ± 1.7 (median 3, range 0-12) and mean duration of flares was 2.0 ± 1.7 months (median 1, range 0-12).There were no differences in number or duration of flares between patients with signs or symptoms on hands only or hands and elsewhere.Demographic and clinical characteristics of patients are shown in Tables 1 and S1.
Current treatments are summarized in Figure 1.The most frequently used treatment was topical corticosteroids, with 38.5% receiving low or medium potency and 62.4% of patients receiving high potency agents.
Patients with eczema on their hands only were less likely than patients with eczema on hands and elsewhere on their body to be treated with a biologic (13.0% vs. 36.5%),oral corticosteroids (17.4% vs. 21.4%), or other oral systemic therapy (11.4% vs. 19.1%),but more likely to be treated with alitretinoin (22.6% vs. 14.8%).
In the stepwise hierarchical approach to indicate the line of treatment used per patient, only 1.9% of patients were treated with topical calcineurin inhibitors alone (with or without antifungals and antihistamines) while 26.7% of patients were treated with topical corticosteroids (with or without topical calcineurin inhibitors, antifungals, and antihistamines but without any other treatments); 62.9% of patients received systemic therapy (excluding oral PDE-4 inhibitors) and 23.4% received biologic therapy (Tables 2, S2 and S3).
There were some significant differences in the use of treatments between countries (Figure S1).

| DISCUSSION
In this multinational retrospective review of 792 patient records, over 60% of patients with moderate to severe CHE were treated with systemic therapy and almost one-quarter of patients were treated with a biologic.Less than one-third (29%) of patients were treated with topical corticosteroids and/or topical calcineurin inhibitors without additional lines of therapy.Treatment differences were observed between patients who had eczema on their hands only and those with eczema on their hands and elsewhere on their body.Differences in treatment approaches were also seen between different countries.CHE is a highly prevalent persistent and fluctuating chronic inflammatory disease that represents a significant burden for patients. 4Despite this, CHE has been described as a neglected disease, with a lack of effective treatments for moderate to severe CHE that can be safely used for long-term disease management. 14In general, guidelines recommend phototherapy or systemic treatments for patients with an inadequate response to topical treatment. 4Alitretinoin is recommended as a second-line treatment but is only approved for severe CHE.Its use may be further limited because it requires medical and laboratory monitoring and should only be prescribed by dermatologists or physicians with experience with systemic retinoids due to several safety concerns, including the need for a strict pregnancy prevention programme in women of childbearing age due to its teratogenic potential. 15Other conventional systemic treatments (e.g., methotrexate, cyclosporin, azathioprine, acitretin) may be considered for patients who are unresponsive to and/or contraindicated for current topicals and alitretinoin but none are specifically licensed for the treatment of CHE and all are associated with potentially severe adverse events.Phototherapy may also be considered but access to treatment and cumulative risk of malignancy limit its use.As such, treatment options for patients with CHE uncontrolled by topical therapy are limited. 16al-world evidence and data (i.e., that collected outside of controlled clinical trials) on the treatment of CHE is sparse.In Germany, the CARPE registry, which was established in 2009 to prospectively assess the management of patients with CHE, reported that 90.5% of 1163 patients at time of inclusion had moderate to very severe CHE and 35.3% were receiving systemic therapy (19.7% alitretinoin) and BORG ET AL.
38.0% ultraviolet phototherapy. 17Systemic treatment (alitretinoin, or off-label acitretin or methotrexate) was prescribed at least once to 39% of 1281 patients during 5-years of follow-up. 6It should be noted that only dermatologists could enrol patients in the CARPE registry, which may explain the high proportion of patients with moderate to severe disease and receiving systemic therapy.An earlier survey of dermatology clinics in Germany that included 223 patients reported systemic therapy use in 11.7%. 18Similarly, a survey of 1203 patients with occupational CHE in Denmark reported that 10% had received systemic therapy, increasing to 13.3% in those with self-reported moderate to severe disease. 19 Sex (female/male/non-binary), n, (%) 395 (49.9)/396 (50.0)/1 (0. hyperkeratotic hand eczema, whereas oral corticosteroids were identified as the most frequent first-line treatment for vesicular hand eczema. 20r data show that over 60% of patients with moderate to severe CHE received systemic therapy, with almost one-quarter received biologic therapy.This is higher than in previous reports but may reflect differences in the patient population, with a higher proportion of patients with severe disease.In addition, patients were primarily treated by hospital-based dermatologists, who may be more likely to see patients with severe disease and to initiate systemic therapy.The increasing availability and acceptance of systemic therapies may also have contributed to their higher use compared with earlier reports.Fewer patients with eczema on their hands only received biologic therapy (13.0% vs. 36.5%),oral corticosteroids (17.4% vs. 21.4%), or other systemic therapy (11.4% vs. 19.1%)compared with those with eczema on hands and elsewhere, while a higher proportion were treated with alitretinoin (22.6% vs. 14.8%).This may be attributed to a tendency to treat more widespread symptoms with systemic rather than topical therapy, as well as labelling differences which are reflected in treatment guidelines and/or reimbursement practices.Biologics (dupilumab, tralokinumab, etc.), cyclosporin, and topical calcineurin inhibitors are all indicated for moderate to severe atopic dermatitis so may have been used in the 40% of patients with atopic aetiology.However, although these treatments are approved for patients with atopic dermatitis and accompanying atopic hand eczema, they are not approved for other types of CHE.
Other oral systemic treatments (e.g., methotrexate, azathioprine, acitretin) are not approved for CHE or atopic dermatitis but are often used off-label.
Oral corticosteroids are primarily used short-term to control flares and bridge to systemic therapy.Use of high potency topical corticosteroids was similar in both the hands only and hands plus elsewhere groups, although fewer patients with hands only signs or symptoms were treated with low-medium potency topical corticosteroids.Use of topical calcineurin inhibitors was also slightly lower in patients with hand eczema only, which may be due to them only being indicated for atopic dermatitis.Topical corticosteroids are typically used to treat flares while topical calcineurin inhibitors may be useful as a steroidsparing approach to maintain remission. 21An alternating combined regimen of a topical corticosteroid for flare control and a calcineurin inhibitor during stable remission may be an option 22 although the long-term safety of such a regimen is unknown. 4fferences in treatments were observed between countries.For as well as differences in national and regional guidelines.
6][27] This is reflected in our data, with alitretinoin the most potent treatment to be used in 30.4% of patients with hyperkeratosis compared to 9.4% without hyperkeratosis.Aetiology and clinical features of CHE can vary considerably between patients, and recent guidelines suggest a better understanding of the relationship between disease subtype and response to different treatments is needed to optimize therapeutic choice. 4It has been hypothesised that retinoids may provide most benefit in hyperkeratotic CHE, while therapies targeting the Th2 inflammatory pathway, for example, dupilumab or tralokinumab, may be more effective in atopic CHE, and pan-JAK inhibitors, for example, delgocitinib, may benefit all sub-types. 4Further investigation into the efficacy of treatments across CHE subtypes is required and is the focus of phase 3 trials, for example, delgocitinib in DELTA 1 and 2 (NCT04871711 and NCT04872101).
This study has several limitations.Firstly, data were assessed retrospectively based on patient records.These patient records were chosen by participating physicians so may have been subject to some selection bias, even though physicians were directed to select their three most recent eligible patients for inclusion, e.g., use of biologics and other systemic therapies may have been overestimated if there was a tendency to select the most actively treated patients.
There may also have been bias in the selection of physicians, both with regard to those invited and those who agreed to participate.For instance, a limit of 35 years in clinical practice was set in an attempt to minimize the number of respondents who might retire in the near future; however, this may have had the effect of excluding older physicians whose prescribing patterns could differ from younger or less experienced colleagues.In addition, differences in eligibility criteria for physicians between countries that were chosen for pragmatic reasons may make cross-country comparisons less valid.Disease characteristics, including signs, were physician-assessed with no patientreported outcomes.Disease reporting is known to differ between physicians and patients. 28Moreover, the order of treatments in the hierarchical analysis is a simplified approach and does not reflect all possible treatment combinations or pathways.
Despite these limitations, the study did include the systematic collection of data for a large number of CHE patients across several countries using a structured questionnaire and the use of patient record forms ensure data are robust.Moreover, to the best of our knowledge these are the first real-world data to be published on the treatment of CHE in a large multinational sample of patients.
In conclusion, these data suggest that, among a sample of patients with moderate to severe CHE predominantly treated by hospital dermatologists, most are on systemic therapy with one-quarter on biologic therapy.Many of these treatments have limited evidence of efficacy in CHE.As such, there remains a need for studies of these therapies specifically in patients with CHE, as well as the development of new treatment options that can provide short-and long-term disease management.
Data were collected using Confirmit (Forsta, London, UK) using a script produced by Ugam Solutions Pvt Ltd, Mumbai, India, based on a design created by Lumanity.Data were anonymised such that only the panel provider M3 Global Research knew the identities of the respondents completing the research.Anonymised data were analysed by Ugam Solutions Pvt Ltd. and Lumanity.The study sponsor LEO Pharma was the recipient of aggregated data.SAS (Release 5.3.1,Proc Univariate, Means and Freq) was used to calculate summary statistics (counts, mean, median, standard deviations, ranges, percentage) for both continuous and categorical variables.
Age >35 years, previous or current atopic dermatitis, and severe eczema were factors related to use of systemic treatment.In a 2013 survey of 194 UK dermatologists, phototherapy and alitretinoin were the most frequent first-line treatment options for T A B L E 1 Demographic and clinical characteristics of patients.Characteristic Overall (N = 792) Hands only (n = 447) Hands + elsewhere (n = 345) Age (years), mean ± SD (median, range) 40.5 ± 13.6 (40, 18-84) 40.6 ± 13.2 (40, 18-82) 40.4 ± 14.0 (40, 18-84) Patients categorized by hierarchical line of treatment received.For example, oral corticosteroid, methotrexate, cyclosporin, retinoids other than alitretinoin.Hands only include wrists.Hands plus elsewhere includes feet and/or elsewhere on body.Other includes anƟfungals.Other oral systemic includes oral corƟcosteroids, methotrexate, and cyclosporin.PDE-4 inhibitors include both topical and systemic (oral) therapies.Hands only includes wrists.Hands plus elsewhere includes feet and/or elsewhere on body.OCS, oral corƟcosteroid; PDE, phosphodiesterase; TCI, topical calcineurin inhibitor; TCS, topical corƟcosteroid.Current treatment for Chronic Hand Eczema.
T A B L E 2 a BORG ET AL.