Abstract
Chronic hand eczema (CHE) is a complex, challenging, and frequently multifactorial skin disease of the hands. It is very common in the general population, especially in certain professions. When hand eczema (HE) persists for longer than 3 months or has a minimum of two relapses per year after initial manifestation with complete clearance, it is considered chronic. In this case, health-related quality of life and the patient’s working life are often impaired. CHE can be considered as an umbrella term because it covers different clinical pictures and etiologies. To date, there is no definite and unique HE classification. Treatment starts with identifying the individual HE etiology paralleled by symptomatic therapy (local and/or systemic and/or ultraviolet phototherapy). Sustainable management of HE requires the identification and avoidance of its triggering factors, from the professional and private environment. This includes ruling out allergic contact dermatitis if any HE persists for more than 3 months despite adequate therapy. Randomized controlled trials investigating the efficacy in HE are lacking for several treatment modalities. Patient education measures of skin protection and prevention complete the multimodal treatment.
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Avoid common mistakes on your manuscript.
Hand eczema is usually a chronic, multifactorial, frequently complicated and challenging skin disease. |
A longer course of hand eczema should prompt consideration of diverse causes. |
Treatment of hand eczema should follow a step-by-step procedure, is generally polymodal, including systemic medication, and should always be accompanied by emollients depending on the status of the skin. |
1 Introduction: Prevalence, Pathophysiology, Etiology, and Clinical Features of Chronic Hand Eczema
Hand eczema (HE) is a common skin disease, with a 1-year prevalence of around 10% in the general population (6.4% in men and 10.5% in women), ranging from mild to severe disease courses [1]. The incidence rate is 5.5 cases per 1000 person-years in adults, with a higher median incidence rate in women (9.6, range 4.6–11.4) than in men (4.0, range 1.4–7.4). The higher prevalence in women is explained by a difference in the distribution of exposure in occupations and private life [1,2,3,4]. A recent systematic review and meta-analysis revealed a lifetime prevalence of 14.5%, a 1-year prevalence of 9.1%, and a point prevalence of 4% of HE in the general population [5]. It can also be shown that the occurrence of HE was 1.5- to 2-fold higher in females than males [5]. More than one-third of patients experienced moderate to severe disease and around one-third had a history of atopic dermatitis (AD) [5]. It is most likely that diagnosing CHE will be supported by molecular diagnostics in the future [6,7,8,9].
The 1-year prevalence of HE was 7.3% for Scandinavian school children aged 12–16 years and 10.0% for adolescents aged 16–19 years [10, 11]. The highest risk factors for 1-year prevalence were self-reported childhood eczema, female sex, and a family history of atopic eczema [11]. The Heidelberg Prevalence Study on HE showed self-reported HE in 6.4% (sample of 1696 subjects), 6.6% of men and 6.3% of women being affected by HE during the last 12 months [12]. As HE in children and adolescents has been rarely studied, some knowledge is missing [13, 14]. The 1-year prevalence is estimated to vary between 5.2 and 10%, with a lifetime prevalence of 6.4–13.3% depending on the child’s age [13]. In a cohort of participants aged ≥ 70 years, 2.7% reported having ever been diagnosed with HE [15].
Chronic hand eczema (CHE) is a complex, multifactorial, and global skin disease with a polymorphic clinical picture occurring worldwide [16,17,18,19]. It is defined by its persistence (longer than 3 months) or its recurrences (at least two relapses per year after its initial manifestation and complete clearance between relapses) [20]. Inflammation of the skin’s epidermis and dermis with a more or less specific pattern of histological and clinical findings is characteristic, depending on the stage of the disease [21]. Histological findings include intercellular edema and spongiosis, acanthosis and parakeratosis in the epidermis, and perivascular infiltrates of lymphocytes in the upper dermis, which may migrate into the epidermis [20]. Primary acute clinical lesions are erythema, edema, papules and vesicles, and rarely bullae [20]. Secondary chronic lesions include crusts, lichenification, hyperkeratosis, scaling, and fissures [20] (see Fig. 1). Itching is the most common symptom in all types of CHE but may vary depending on the type of CHE. According to the author’s clinical experience, patients with atopic CHE report the highest severity of itch. Pain, burning, and stinging of the skin, as well as a mixture of sensations, may also occur in CHE [19]. HE may be located anywhere on the hands and wrists, sometimes limited to certain parts of the hands such as the palms, interdigital spaces, and fingertips. According to cIinical experience, involvement of the palms and wrists are typical for atopic CHE, whereas interdigital spaces and the back of the hands are characteristic of irritant CHE. A large extent at the onset of HE indicates a bad prognosis [20, 22].
21-year-old shopkeeper with chronic hyperkeratotic hand eczema
Histology and clinical morphology rarely allow for definitive conclusions about the underlying etiology of the patient’s HE. Furthermore, the clinical picture may change over time with increasing disease duration despite the etiology remaining consistent [20, 23]. Frequently, more than one etiological factor is found to play a role in the development of the disease, e.g. irritant contact dermatitis (ICD) is often found together with allergic contact dermatitis (ACD) and atopic HE [18, 20] (see Fig. 2). This also complicates the classification of HE [20]. According to a consensus-based recommendation from the European guideline on HE [20], HE is divided into etiological and clinical subtypes, as shown in Table 1.
42-year-old physiotherapist with a atopic hand eczema and b atopic eczema on the neck
Lifestyle factors are an important issue in CHE. Smoking has been frequently described as an important aggravating factor, especially for vesicular HE [24]. It has been shown that smokers have more severe CHE and more days of absence from work [24]. A meta-analysis including 17 studies found low-quality evidence that smoking is associated with a higher prevalence of HE [25]. Additionally, no convincing evidence of associations for other lifestyle factors, e.g. physical activity, body mass index, and alcohol consumption, was found [25]. According to the author’s own clinical observations, in very chronic, long-lasting and severe CHE, stress appears to be an important factor for chronic disease course. This association is currently under investigation.
ICD is more frequent and more likely than ACD in both occupational and non-occupational settings [26]. It is difficult to differentiate clinically between ICD and ACD, but taking a patient’s history may help. Patch testing is often required for definitive diagnosis [26]. ICD of the hands is the result of often repetitive exposure to irritants on the skin [20]. Irritant skin reactions are non-specific, with varying inflammatory reaction, depending on the intensity and duration of exposure and the individual resistance level of the skin [20]. The absence of spreading, and location on the interdigital space and the back of the hands/fingers, are often indicative for ICD [20]. Wet work [27,28,29] is the main cause of ICD, and the risk is positively correlated with duration and frequency of exposure [20, 30, 31]. Determining and quantifying exposure to irritants is necessary by taking a careful history (e.g. number of hand washes and use of skin cleansers, hours of wet hands per day, use of occlusive gloves, contact to skin-irritating substances) [20]. Physical factors may include repeated mechanic strain, skin abrasion, and thermal damage (cold and/or heat) [20]. Chemical factors causing skin damage include corrosive substances (acids, alkalis) or cellular toxins. Contact with irritant chemicals can in some cases be identified by reviewing the safety data sheets, but often these are not meaningful or conclusive [32]. During the last few years, hot summers in Western countries (i.e. the United States and Europe) appear to aggravate vesicular HE in AD patients, frequently affecting not only the palms but also the soles. The impact of climate change on HE has not been investigated yet and therefore cannot be estimated at present.
HE is the most common occupational skin disease, with a prevalence of up to 40% in high-risk occupations [20, 33]. This includes wet-work occupations (e.g. healthcare workers, metal workers, hairdressers, and cleaners) and also occupations with more mixed exposures (e.g. the food industry, metal workers, florists) [20, 34, 35]. Common prevention standards were recently developed in a European consensus process, including case definition, reporting, and surveillance recommendations [33]. The adoption of these may contribute to better understanding of the occurrence and frequency of occupational HE (OHE) [20].
A study showed that 28% of HE patients were absent from work; 12% of cases for more than five consecutive weeks [36]. Another study showed that 57% of patients with OHE had a period of sick leave in the past 12 months, 44% reported a job change, 15% were taking early retirement, and 72% suffered impairment of health-related quality of life (HRQoL) [20, 37]. Severe OHE, age ≥ 40 years, and severe impairment of HRQoL at baseline predicted long-term sick leave and unemployment [20, 37], which were comparable with the impairment caused by psoriasis or asthma [37, 38]. The negative impact is greater for women than men [39], with a higher likelihood of depression among women [40], as well as in metropolitan than non-metropolitan patients [20, 41]. HE patients reported significantly higher levels of distress, suicidal ideation, depression, and anxiety than controls in a European study [20, 42].
HE has a substantial health economic and sociomedical impact due to considerable occupational, domestic, social, and psychological consequences [43]. A recent systematic review and meta-analysis demonstrated that HE has a moderate-to-severe impact on quality of life, with a strong correlation between disease severity and impact on quality of life [44]. A systematic review comparing cost-of-illness of HE showed that the mean total yearly costs per patient varied between €1311 and €9792, with higher costs with more severe HE and OHE [20, 45]. Working while being sick may have an even greater influence on costs, with a 1-year prevalence of 41% in HE patients [46].
2 The Challenge of Diagnosing Chronic Hand Eczema
Diagnosing CHE usually includes a medical history, clinical examination, and skin tests [20, 47]. It starts with careful history taking, including personal and occupational exposures (current and previous), and clinical examination of the hands and the entire skin [20]. Contact allergy should be ruled out, especially when the time course, a duration of longer than 3 months, and the location are suspicious for it [48]. Diagnostic tests include patch testing of baseline series, occupational and further selected series, and the patient’s own substances (e.g. protection gloves, lubricants, creams, cosmetics), and possibly skin prick tests depending on occupational and private exposures. Depending on the clinical picture, microbiology tests and skin biopsy may be indicated. However, for differentiation of psoriasiform eczema from eczematized psoriasis, a histological assessment normally does not contribute. Reliable methods to distinguish both diseases and, in particular, to monitor treatment success, as well as the disease course and long-term control, are still lacking [49]. New molecular methods may help to better differentiate eczema and psoriasis, e.g. the disease-specific expression of the genes NOS2 and CCL27 is used for this purpose [50].
2.1 Medical History
Medical history should include first signs and symptoms, course and time of HE, exacerbations and remissions in relationship to work, and absence from work, as well as specific work-related and private activities and exposures, personal and family history of AD, previous and concurrent skin or systemic diseases, regular use of medication, and regular smoking habits [20]. Information on previously documented allergic sensitizations and test procedures should be obtained [20]. Current and previous occupations, wet work, hobbies, household activities, and care of relatives should be queried [51, 52].
2.2 Clinical Examination
Clinical examination requires the inspection of the hands as well as the whole skin, especially the feet. The clinical manifestations and differential diagnosis of CHE are broad and comprise a whole spectrum of different entities such as psoriasis, lichen planus, tinea manuum, secondary syphilis, scabies, cutaneous T-cell lymphoma, drug eruption, pityriasis rubra pilaris, porphyria cutanea tarda, palmoplantar keratodermas, and Bowen´s disease [53].
Diagnosing CHE should always include the subjective perception of the patient and the individual’s opinion on its cause. This may help to identify unexpected or unusual etiologies, especially in contact dermatitis. A recent study showed that the patient’s perspective and the assessment of the individual disease in daily dermatological care of CHE differs between patients and dermatologists [54].
2.3 Diagnostic Tests
Assessment of exposure to contact allergens and irritants, qualitatively and quantitatively, is important to facilitate planning of skin test strategies, make a correct diagnosis, and establish preventive measures and a treatment plan [20].
2.3.1 Allergy Testing
Epicutaneous patch testing is the gold standard for diagnosis of contact allergy [20]. Patch tests should be performed in all patients with HE who are not responsive to adequate treatment and with a clinical suspicion of contact allergy [20]. Clinically relevant contact allergies cannot be predicted based on the pattern or severity of dermatitis, but they should be based on exposure, location of dermatitis, and often with vesicular morphology supporting an etiology [20, 36, 55, 56].
Patch testing and the substances to be tested should be selected according to the patient’s history and occupational and private exposures [20, 48, 57, 58]. The European Society of Contact Dermatitis (ESCD) guidelines on epicutaneous patch testing describe how patch testing should be practically planned and performed [59]. Any positive patch test reaction requires a careful evaluation [20]. If contact allergy is still suspected despite negative tests, less standardized techniques such as a repeated open application test (ROAT) can be performed in experienced centers [59,60,61]. After patch testing, exposure analysis should be performed. It should be ruled out if current or previous exposures to allergens and/or irritants have caused the present dermatitis and to suggest preventive measures, if relevant (also see Sect. 3 on ‘Prevention’). Analysis of ingredients in products labels and safety data sheets is a common and straightforward method for identification of allergens [20]. It may also be necessary to contact the manufacturer of the patients’ products, such as protective gloves [56]. Nickel exposure or deposition can be assessed using the dimethylglyoxime test, e.g. by employing it in work tools or directly on the hands in cases suspected of occupational ACD to nickel [62].
If contact urticaria is suspected in HE patients, e.g. due to natural rubber latex gloves or proteins from plant or animal foods [6], skin prick testing (SPT) is a first-line approach; however, the washout periods for topical and systemic medications need to be considered to avoid false-negative test results [7]. Prick-to-prick testing is the method of choice when testing fresh foods and plant or animal material. When protein contact dermatitis without systemic symptoms is suspected, the prick-to-prick test with fresh proteinaceous material (foods and plants) can be used as a diagnostic tool [20]. Alternatively, direct exposure, for approximately 20 min, to fish or meat on the finger where protein contact dermatitis occurs may lead to wheals and vesicles and thus support the diagnosis [20]. In patients who have had generalized symptoms previously, the risk of anaphylaxis should be considered. In this case, in vivo tests should be performed under special precautions (emergency medication and equipment must be available and staff must be familiar with them) [20]. Test reading must be performed by an experienced person because non-specific or irritant test reactions may occur. Expertise is needed for proper interpretation of patch test reactions. The measurement of specific IgE provides complementary information on the individual sensitization profile [20]. Finally, the patient’s symptoms, skin tests, and IgE must be interpreted together and in consideration of their clinical relevance.
2.3.2 Microbiology Tests
If a skin infection is suspected, skin scrapings for culture, microscopic evaluation, and, where necessary, PCR should be performed to rule out mycoses. In patients suffering from CHE and tinea pedis, so-called ‘two feet-one hand syndrome’, must be considered [8]. Especially in atopic HE, Staphylococcus aureus (S. aureus) can be a concomitant or aggravating factor of HE [20]. Signs of clinical infection should be the main driver for antibiotic treatment prescription [9, 20]. Scabies should be considered [20]. Exceptional locations, e.g. vesicles on one finger, may be herpes simplex infection [63]; papules and keratosis on one finger may be verrucae [20].
2.3.3 Skin Biopsy Examination
Skin biopsies may be helpful to rule out differential diagnoses (e.g. lichen planus, lymphoma) but in particular, differentiating eczema and psoriasis of the hands is still a challenge. Basic research and opinion statements on new developments in molecular diagnostics are currently focusing on CHE [64]. The first molecular classifier to distinguish psoriasis from (hand) eczema signature has been introduced as CE-marked in vitro diagnostics (CE-IVD), but many more biomarkers are currently being investigated. This molecular classifier is currently applied in a cohort of OHE patients and first results show a great benefit for diagnosing and treating CHE [65, 66]. In the future, diagnosis of CHE will be supported by molecular diagnostics [64]. Transcriptome analysis using RNA sequencing has been described to better understand biological processes in CHE [67]. Lesional vesicular HE (VHE) showed a distinct expression profile compared with non-lesional skin and healthy control skin [67]. Further analysis indicates a common pathophysiology between VHE and AD, and also reveals transcriptional differences between vesicular HE and HE in AD [68].
2.4 Scoring and Documenting Hand Eczema and its Impact
Numerous outcomes and measurement instruments are used in HE trials. Scoring and documenting HE and CHE are challenging, especially for clinicians, and patients and physicians may have different points of view [54]. The heterogenicity of patient- and physician-reported outcomes limits the evidence synthesis concerning therapeutic and preventive interventions [69]. The Hand Eczema Core Outcome Set (HECOS) initiative is an international working group of dermatologists and researchers experienced in HE trials aiming to develop a core outcome set for future trials [69, 70]. The view of patients is considered and has shown to be of great importance when selecting domains such as symptoms and HRQoL [70]. A panel of stakeholders will meet and select core domains in September 2024 [70].
The Task Force of the European Academy of Dermatology and Venereology for occupational skin diseases recommends the use of the Dermatology Life Quality Index (DLQI) and the 36-item Short Form survey (SF-36) as generic instruments in HRQoL studies on occupational skin disease [71]; however, recent research has demonstrated that disease-specific instruments are needed [72, 73]. The Quality of Life in Hand Eczema Questionnaire (QOLHEQ) is used to assess HRQoL in patients with HE, according to the domains of symptoms, emotions, functioning, and treatment/prevention; however, according to a comprehensive conceptual model illustrating the signs, symptoms and impact of CHE, a new instrument is currently under development [73, 74].
3 Prevention
Prevention consists of primary, secondary, and tertiary prevention strategies [20, 42]. Primary prevention is directed at the healthy population and aims to decrease the number of new cases of HE [20]. Secondary prevention addresses HE patients with a rather short history of (mild) signs and symptoms [20]. Measures of prevention should be introduced as early as possible to prevent a progression or relapse of HE [20]. Tertiary prevention targets patients with severe CHE to reduce the severity of the disease, to optimize measures of prevention, and to prevent chronicity, days of sick leave and the development of adverse sequelae (e.g. by medical or occupational rehabilitation) [20]. All this can be realized with trained staff such as dermatologists, co-workers in health education, and specially trained nurses.
Measures of prevention should aim to identify and subsequently reduce or eliminate occupational and non-occupational causative exposures [20]. Endogenous and other individual risk factors should be considered [20]. Preventive measures differ between countries depending on the health care system and the regulatory and economic situation [20, 75]. Examples are EU regulations on occupational safety and health [75] or on exposures to contact allergens such as chromium in cement and leather, nickel in jewelry and other personal items [76,77,78,79], and methylisothiazolinone in personal hygiene products and cosmetics [80]. Risk assessment is necessary for detecting and subsequently minimizing harmful skin exposures [20, 33]. The STOP principle describes the suggested hierarchy of prevention measures [20], including substitution (S) of hazardous exposure with a safer product/substance; technological (T) measures such as automation, absorption of dust, and elimination of a contact allergen (e.g. in metalworking fluid, gloves); organizational (O) measures such as equal distribution of hazardous work; and (P) personal protective equipment (PPE), e.g. protective gloves, protective clothing, and face masks. PPE should be used according to risk assessment and safety standards [20], e.g. protective gloves may contain rubber additives that can cause ACD [20, 81, 82]. Inadequate equipment or failure in the instruction and use of adequate equipment may result in the development or worsening of HE [20]. Regarding skin barrier creams, evidence for their efficacy [83, 84] is limited and they should be selected according to the irritant (e.g. water- or oil-based substance), otherwise they may intensify signs and symptoms of HE [20, 85,86,87]. Skin barrier creams are not well-defined, vary in composition, and are not well-differentiated from emollients [20]. In a large, prospective intervention study of 1020 metalworkers, with a 12-month follow-up, the use of both skin barrier cream and after-work emollient showed the best improvement of HE [88]. A Cochrane review described that emollients used alone or in combination with barrier creams may result in a clinically important protective effect for the primary prevention of irritant OHE [20, 89]; however, it was concluded that there was insufficient evidence to confidently assess the effectiveness of interventions in the primary prevention of irritant OHE based on the use of barrier creams, emollients, or health education [89].
Raising awareness and educating people on HE (e.g. patient trainings, leaflets, social media) and the use of PPE are important strategies to improve the individual’s motivation, their ability to use appropriate protection measures, and to maintain a feeling of empowerment (taking responsibility for their own health and demonstrating the power of influencing skin health) [20]. It is important to inform patients how to avoid relevant allergens/allergen sources in the case of ACD [20]. Table 2 describes practical recommendations to prevent HE and to educate patients on adequate skin protection behavior as early as possible [20]. Even though there is currently insufficient evidence for the effectiveness of health education in primary prevention of work-related HE [89], it is supported by several controlled prospective studies in apprentices [20, 83, 85, 87,88,89,90,91,92,93,94]. Individuals with previous or current AD are particularly at risk of developing HE. Measures of secondary prevention of work-related HE based on health education and PPE failed to show a clear benefit [95,96,97,98,99]; however, particular face-to-face education has been reported as an effective secondary prevention strategy in patients with HE [20, 100, 101], especially in high-risk occupations [102,103,104]. The author’s clinical experience and data indicates that health care workers need more focused information and education [95]. ‘Hands-on’ skin protection seminars are an effective standard procedure in the management of patients with OHE, showing good results in decreasing disease severity and allowing continuation of the profession [105,106,107]. It is important to start these interventions as soon as possible because they are more effective in mild to moderate HE compared with severe cases [100, 107]. When secondary prevention fails, or in patients with a severe disease course, a tertiary individual prevention program (TIP) is offered in Germany [108]. The TIP is based on a 3-week inpatient phase in a specialized center providing intensified diagnostics and treatment, health education, and psychological counseling. This is followed by a 3-week outpatient phase allowing full recovery of the skin barrier before returning to work [108]. The TIP is associated with sustained improvements in disease severity, ability to work, HRQoL, and prognosis [108]. A recent systematic review investigated the short- and long-term effects of these German secondary individual prevention programs (SIPs) and TIPs for occupational skin diseases [109]. Primary outcomes were continuation of employment, severity of hand dermatitis, and HRQoL. A total of 19 studies encompassing 5527 patients with occupational skin disease were included (11 studies on SIP, 8 studies on TIP). Following the SIP, approximately 70–90% and 60–70% of patients remained in their occupation after 1 and 5 years, respectively; 82.7% of patients remained in their occupation and exhibited a significant decrease in hand dermatitis severity and HRQoL 3 years after the TIP [109]. In conclusion, secondary prevention strategies are recommended to be started as early as possible in already-affected individuals to prevent relapse or progression of HE, and tertiary prevention programs are recommended in those with severe CHE to decrease the severity of the disease and to improve long-term control [20, 108].
4 Treatment
Treating HE depends on the severity, etiology, morphology, and location of HE, comorbidities, and, if possible, identification and avoidance of causal exogenous factors such as allergens and irritants (Table 3) [20]. Acute HE should be treated immediately to avoid chronicity, using topical anti-inflammatory agents and emollients [20]. Full regeneration of the epidermal barrier takes several weeks or months. Patients must be advised to avoid re-exposing the skin before complete healing and stabilization of HE, and that prolonged exposure to potent topical corticosteroids may further impair the skin barrier function [20]. The skin barrier on the palms needs more time for recovery compared with palmar locations [20]. Treating CHE means a multimodal treatment concept including topical and systemic treatment together with general measures such as continuing use of emollients [20]. Patients tend not to use topicals when receiving a systemic treatment, and not to use emollients when topical treatment is started with glucocorticoids and immunomodulators [20]. A Cochrane review [110] identified 60 randomized controlled trials (RCTs) with a considerable heterogeneity in the use and duration of treatments, outcome measures, and long-term control. Only 24 studies included a follow-up period [20].
4.1 Topical Treatments
Emollients/moisturizers are used for the treatment of HE but evidence of their efficacy is limited [20]. A Cochrane review [110] included two small studies on the protective use of emollients [88, 89] but no conclusions were drawn on efficacy. Three additional studies [111,112,113] showed that emollients may reduce severity and itch. There is no evidence that supports the use of any specific moisturizers in HE [110, 114, 115], however emollients are used in HE to maintain and/or improve skin barrier function [20]. The preference of the patient as well as existing (contact) allergies must be considered [20]. Use, acceptance, and compliance with emollients/moisturizers can be improved when easy accessibility (for example, in a dispenser in an easily accessible place) along with clear instructions on how, when, and which product to choose are provided [20].
Depending on national practices, tanning substances (lotion, cream, bath, e.g. Tannolakt®, Tannosynt®) and topical antipruritic substances such as menthanol and urea (preferentially in hyperkeratotic CHE) complement topical treatment modalities.
4.1.1 Topical Glucocorticoids
Along with emollients, topical glucocorticoids are the topical treatment of choice for HE. A Cochrane review on HE included nine studies on topical glucocorticoids [110], with six studies of very short duration (≤ 3 weeks), and mostly compared two glucocorticoids or compared the same glucocorticoids in different vehicles, dosages, or application frequency [20]. All showed a reduction in disease severity. Clobetasol foam yielded favorable participant-rated disease control versus vehicle after 15 days [116], but skin atrophy is frequent, especially when treatment cycles are repeated. The only study with a longer duration (36 weeks) assessed disease control with mometasone twice per week versus thrice per week versus no mometasone, after having reached remission [117]. Thrice-weekly mometasone may work slightly better than twice-weekly [117], with only a few reports of mild atrophy.
Potent topical glucocorticoids have been shown to inhibit repair of the stratum corneum, in part due to filaggrin degradation [118,119,120], and may cause skin atrophy in long-term use [20]. The therapeutic index describes the ratio between desired and non-desired effects, especially skin atrophy, and should be considered particularly in long-term use topical glucocorticosteroids [121]. Mometasone appears to be moderately potent with fewer adverse effects [122], and once-daily treatment is sufficient and may even be superior to twice-daily application [123]. Intermittent dosing may reduce the risk of skin atrophy but there is little evidence to support this [117]. Clinical experience indicates that alternating or combining a topical glucocorticoid with a topical calcineurin inhibitor may be considered in an attempt to reduce adverse effects [124], although the long-term safety of this approach is unknown [20]. The addition of topical glucocorticoids increased the efficacy of systemic treatment with alitretinoin [125].
4.1.2 Topical Calcineurin Inhibitors
The topical calcineurin inhibitors tacrolimus and pimecrolimus are licensed for the treatment of AD but not for HE of other etiologies [20]. A Cochrane review on HE included four small studies on tacrolimus and five larger studies on pimecrolimus (duration ≤ 8 weeks) [110]. Burning or itching may occur in initial tacrolimus treatment and when erythema and vesicles are dominating. Data for pimecrolimus 1% are conflicting and there were no significant differences in efficacy between pimecrolimus and placebo [20, 110]. As the skin barrier on the palms differs from that on the back of the hands, the large calcineurin inhibitor molecules may penetrate better on the back of the hands, potentially resulting in better efficacy [20].
4.2 Physical Therapies
4.2.1 Phototherapy
Ten studies on ultraviolet (UV) therapy were included in the Cochrane systematic review [110], but the heterogeneity regarding interventions, comparators and outcome measures did not allow a meta-analysis to be performed. Psoralen plus UVA (PUVA) performed as bath or cream [126, 127] seems to be similarly effective. UVA1 may also be effective [128,129,130] but availability is often limited [20]. Adverse events of phototherapy include erythema and burning of the skin, and long-term use increases the risk of non-melanoma skin cancer [131].
4.2.2 Iontophoresis
Tap water iontophoresis is very effective for treating hyperhidrosis and acrocyanosis of the hands (and feet) [20]. Treatment must usually be started twice daily for 10–15 min, which is frequently perceived as stressful and time-consuming by patients; however, motivation can be raised when patients see and feel the improvement because hyperhidrosis is frequently felt as embarrassing and restricts several activities in a patient’s professional (e.g. wearing protective gloves) and private life (e.g. social contacts, shaking hands). Once hyperhidrosis is improved, the frequency can be reduced to once-daily and every-other-day treatment. Long-term control can be achieved when tap water iontophoresis is maintained twice weekly.
4.3 Systemic Treatment
4.3.1 Oral Corticosteroids
No RCTs on oral corticosteroids in treating HE were identified [110]. According to clinical experience, they are very effective in acute HE and also improve CHE, but long-term or repeated use does not help the long-term control of CHE and may lead to long-term adverse events and immediate disease relapse, especially if no etiology-focused treatment is introduced in parallel. Emollients and, for example, tanning substances should be used at the same time. Oral corticosteroid treatment should be limited to a maximum of 3 weeks, beginning at 0.5 mg/kg bodyweight/day (dosage for prednisone), with a tapering-down schedule.
4.3.2 Alitretinoin
Alitretinoin is an oral vitamin-A derivative (retinoid) and is the only systemic treatment that is licensed for the treatment of CHE (severe CHE that inadequately responds to treatment with [very] potent topical corticosteroids) [20]. Four studies with alitretinoin at daily doses of 10 and 30 mg versus placebo showed that the 30 mg dose is significantly better in controlling CHE [110]. Patients should also use emollients. The 10 mg alitretinoin dose should be used when 30 mg is not tolerated or when significant adverse effects, e.g. hyperlipidemia, limit the 30 mg dose. The most frequent adverse event is headache, especially with alitretinoin 30 mg daily. Other adverse effects are an increase in plasma cholesterol and triglyceride levels and a decrease in thyroid function parameters, and these should be monitored at least once a month during therapy [132]. Alitretinoin is teratogenic and therefore pregnancy prevention measures are indicated during treatment, for which the information in the summary of product characteristics (SMPC) and local guidelines must be followed (e.g. in Germany, 4 weeks before and after treatment) [20].
Research and clinical experience demonstrate better effects with alitretinoin in hyperkeratotic types of CHE [133, 134]. In a study comparing azathioprine with alitretinoin, a high number of adverse events was observed, leading to a high dropout ratio and premature discontinuation of the trial [135]. Alitretinoin is licensed for a 3- to 6-month treatment and should be stopped after 3–4 months if no adequate effect has been observed [133]. In patients who responded well to a first treatment but then experienced a relapse, retreatment was effective, and extending treatment beyond 24 weeks may be beneficial in those who experience improvement, but not complete healing, within the first 24 weeks [136, 137].
4.3.3 Acitretin
Acitretin is not licensed for the treatment of HE and data on its efficacy in HE are limited [20]; however, it can be used in hyperkeratotic CHE when alitretinoin treatment has failed. One 8-week placebo-controlled study with 30 mg/day was included in a Cochrane systematic review [110, 138]. After 4 weeks the presence/severity of hyperkeratosis, fissuring, scaling, itch, redness and vesicle count was reduced (51% reduction in clinical symptoms), with no further improvement in longer treatment periods.
Acitretin is teratogenic and therefore pregnancy prevention measures are indicated during and after treatment, for which the information in the SMPC and local guidelines must be followed (e.g. in Germany, 4 weeks before and 24 weeks after treatment) [20]. There is no established dosing and time duration for CHE treatment. A dosage of 0.3–0.5 mg/kg bodyweight/day (preferentially applied in two doses) for 4–8 weeks, and then 0.5–0.8 mg/kg bodyweight/day daily can be applied for 3–4 months. If effective, the dose can be lowered and continued [20]. When complete healing of CHE is achieved, acitretin may be discontinued. According to our clinical observations, long-term control can be achieved if general protective measures and emollients are implemented completely and reliably.
4.3.4 Cyclosporine
In some countries, cyclosporine is licensed for use in AD but not specifically for HE [20]. One small, 6-week study assessing the efficacy of cyclosporine 3 mg/kg/day versus topical betamethasone dipropionate 0.05% in 34 participants with HE favored cyclosporin slightly [110, 139]. In an open-label study, cyclosporine (3 mg/kg bodyweight/day) achieved a 1-year success rate of 74% in CHE of unspecified severity [140]. A recent retrospective study comparing both cyclosporine (3–5 mg/kg/day) and alitretinoin (30 mg/day) for 24 weeks showed responder rates of 40.9% for cyclosporine and 68.2% for alitretinoin [141]. Patients with impaired renal function, malignancy, and uncontrolled hypertension should not be treated with cyclosporine. Cyclosporine treatment requires careful monitoring, especially concerning adverse effects such as increase of blood pressure, nephrotoxicity, headache, hyperlipidemia, risk of infection, and gastrointestinal adverse effects. Cyclosporine should be discontinued if no effect has been observed within 8 weeks [20].
4.3.5 Azathioprine
Azathioprine is not licensed for HE [20]. One single-blind RCT compared topical clobetasol versus clobetasol plus azathioprine 50 mg/day, with better outcomes after 24 weeks in the group with additional azathioprine treatment [142]. Azathioprine can be started at a dose of 1 mg/kg bodyweight/day orally, increased up to 3 mg/kg bodyweight/day for a minimum of 3 months, and may be used as a long-term treatment at the minimum effective dose.
4.3.6 Methotrexate
Methotrexate is not licensed for use in CHE and no RCTs have been conducted [20]. Two retrospective studies on the use methotrexate in CHE, with a low number of patients, reported ‘almost clearance’ after 12 months [45, 143]. Hyperkeratotic HE may respond better. A dosage of 7.5 mg orally per week may be started and can be increased to 25 mg orally per week. A randomized, open-label trial in 42 patients with severe CHE (without hyperkeratotic HE) was prematurely discontinued, showed a high withdrawal rate of 57.1%, and confirmed that methotrexate has a high number of adverse effects and is frequently ineffective [20].
4.4 Further Treatments
Although HE is a highly prevalent disease, fewer evidence-based treatment studies are available compared with other chronic inflammatory diseases such as psoriasis or AD [144]. As the number of treatments for AD has steadily increased, some of these new treatments may also address CHE, especially atopic CHE [145]. Future studies will investigate their efficacy and will also demonstrate if combination treatments, e.g. with topical glucocorticoids, are necessary and/or beneficial.
4.4.1 Dupilumab
Dupilumab, a human monoclonal antibody inhibiting interleukin (IL)-4 and IL-13 signaling, is used for the treatment of AD [20]. A label enrichment to atopic hand and foot dermatitis was introduced in Germany in October 2023.
A clinical study with 133 participants with moderate-to-severe atopic hand and foot dermatitis was recently published [146]. Results showed an acceptable safety profile and a significant improvement of pruritus (peak numerical rating scale [NRS]) and severity of hand/feet skin lesions versus placebo. Small observational studies and case reports show a favorable response of HE to dupilumab in patients with atopic HE, and possibly in patients with vesicular and hyperkeratotic HE [147,148,149,150]. In the prospective, observational study of patients with AD and concomitant HE, a minimal reduction of HE severity was reported [149]. One RCT contained 29 patients with severe CHE who had an inadequate response/intolerance to alitretinoin, or when alitretinoin is medically inadvisable (dupilumab n = 20, placebo n = 9). At week 16, more patients achieved HECSI-75 (at least 75% improvement in the Hand Eczema Severity Index score) in the dupilumab group than in the placebo group {95.0% (95% confidence interval [CI] 73.1–99.7.0%) vs. 33.3% (95% CI 9.0–69.1%)}. Dupilumab also showed greater least square mean percentage change from baseline to week 16 in peak pruritus NRS than placebo (− 66.5 ± 10.7 [95% CI − 88.6 to − 44.5] vs. − 25.3 ± 17.0 [95% CI − 60.1 to 9.4]). Adverse events were similar between the dupilumab and placebo groups and were mostly mild; none of them lead to discontinuation [151]. Dupilumab was considered efficacious and well tolerated. Another recent retrospective, multicenter study investigated dupilumab in hand and foot eczema in 84 moderate-to-severe AD patients [152]; 86.7% showed a reduction in HE severity (by Physician Global Assessment [PGA]) and 80.3% in PGA-Foot. NRS-itch reduction ≥ 4 was reached in 73.0% of patients at week 16 and 80.8% at week 52 [152].
In conclusion, from retrospective and prospective studies, dupilumab seems to be a promising therapeutic option for refractory CHE in patients with and without AD, but studies of longer duration in larger cohorts of patients, and also considerning different clinical subtypes or etiologies of CHE, are needed [153].
4.4.2 Delgocitinib
Delgocitinib, a topical pan-Janus kinase (JAK) inhibitor, was reported in a randomized, double-blind, phase IIa study with delgocitinib ointment 30 mg/g [154]. Patients with unclassified CHE were treated for 8 weeks and results suggested delgocitinib to be an efficacious and well-tolerated topical treatment [20]. No plateau of efficacy was observed, therefore longer treatment may result in further improvement. Furthermore, delgocitinib in a cream formulation was studied in CHE in a 16-week randomized, phase IIb trial [155]: 258 patients were randomized to delgocitinib cream 1, 3, 8, and 20 mg/g or vehicle. There was a significant dose-response relationship, and delgocitinib 8 and 20 mg showed a significant treatment effect versus vehicle. There were also improvements in severity, itch and pain. Delgocitinib cream was well tolerated. The most frequently reported adverse events were nasopharyngitis, eczema, and headache [155].
A recent analysis assessed 11 signs and symptoms of CHE daily through the Hand Eczema Symptom Diary (HESD) using an 11-point numeric rating scale; this was an exploratory endpoint [156]. Delgocitinib cream 20 mg/g was associated with an early and sustained reduction in itch and pain, along with clinically relevant reductions of ≥ 4 points from baseline to Week 16 in 48.4 and 63.6% of patients, respectively (17.9 and 5.9% with cream vehicle, respectively). There were improvements versus cream vehicle in all assessed CHE signs and symptoms (20 mg/g, p < 0.05) [156]. These data correlated with clinician-reported outcomes, indicating that the HESD may be a useful assessment tool for CHE management [156]. According to the EU Clinical Trials Register, five additional studies with delgocitinib cream (20 mg/g) are currently ongoing for the indication of CHE: two phase III studies with adults and one phase III study with adolescent study participants (12–17 years), as well as a phase III extension study with adults to investigate long-term safety with twice-daily treatment with delgocitinib cream 20 mg/g as needed. In addition, there is a two-arm, phase III study in adults comparing delgocitinib cream (twice daily) versus alitretinoin orally.
4.4.3 Baricitinib
Baricitinib, an oral JAK-1 and -2 inhibitor approved for adults with moderate-to-severe AD was effective in two cases of hyperkeratotic and severe atopic CHE using 4 mg daily [157]. The dose may be tapered to 2 mg daily. Emollients were continued and topical glucocorticoids were used at < 10 g/week [157]. Similar results were confirmed in nine patients with recalcitrant CHE and foot eczema who were treated with baricitinib after an inadequate response to low-dose cyclosporine [158].
4.4.4 Upadacitinib
Upadacitinib is an oral JAK-1 inhibitor that produced significant improvements in mild-to-severe CHE in patients with moderate and severe AD in an observational cohort study [159]. Upadacitinib 15 mg once daily was administered in 32 CHE patients; in those with severe clinical disease, 30 mg was administered initially and reduced to 15 mg when effective [159]. Another study evaluated the 16-week effectiveness and safety of upadacitinib on CHE in patients with moderate-to-severe AD. Similar results were obtained with upadacitinib 15 and 30 mg monotherapy in improving atopic HE compared with placebo [160]. At Week 16, the observed mean improvements in HECSI score in upadacitinib-treated patients were clinically meaningful based on previous interpretability studies. Upadacitinib may be an effective treatment option for atopic HE in patients with moderate-to-severe AD [160].
4.4.5 Ruxolitinib
Ruxolitinib, a potent JAK-1/JAK-2 inhibitor, can be administered orally or topically [161]. Topical 1.5% cream is approved by the US FDA for the short-term and non-continuous chronic treatment of mild-to-moderate AD in non-immunocompromised patients > 12 years of age. Two phase III clinical studies (TRuE-CHE1 and TRuE-CHE2) have been withdrawn for business reasons [161].
4.4.6 Gusacitinib
Gusacitinib is an oral, dual pan-JAK/spleen tyrosine kinase (SYK) inhibitor. It showed dose-dependent improvement in moderate-to-severe CHE up to 16 weeks compared with placebo in a phase IIb study [161]. Patients were randomized to gusacitinib 40 or 80 mg or placebo once daily. Gusacitinib was well tolerated. Nasopharyngitis, nausea, and headache were reported as adverse effects.
4.4.7 Apremilast
Apremilast, an oral phosphodiesterase inhibitor, was administered for 3 months (30 mg twice daily) in patients with hyperkeratotic hand and foot dermatitis in a randomized controlled study involving 77 patients [162]. One group (39 patients) received mometasone furoate 0.1% cream with oral apremilast and another group received mometasone cream alone (38 patients). HE severity decreased significantly in both groups. Complete clearance was achieved in 6 patients treated with apremilast and 1 patient treated with mometasone cream alone.
Other treatments being investigated for AD may also soon be investigated in CHE, including nemolizumab (anti-IL-31), fezakinumab (anti-IL-22), etokimab (anti-IL-33), and JNJ-39758979 (histamine H4 receptor antagonist). Since etiology, morphology, and individual features of CHE vary between patients, more research on different subgroups of CHE and their response to different drugs is needed [20].
5 Conclusion
Based on clinical experience and research, hyperkeratotic CHE benefits more from retinoids, atopic CHE appears to benefit more from T helper-2-targeted therapies such as dupilumab and tralokinumab, and pan JAK inhibitors may benefit all types. More evidence needs to be gained by robust clinical research that takes subtypes/endotypes into account, while reporting consistently validated and comparable outcomes [20]. Patient- and physician-reported outcomes should also be more consistently used in HE clinical studies, and new results from the HECOS initiative showed, for example, that itch was rated highly by patients with CHE [70]. Considering the burden of disease of CHE, improved insight and evidence is greatly needed in the general and specific patient populations with this condition [20].
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The author thanks Mrs. Heike Grönebaum and Mr. Philipp Bentz, MSc, Heidelberg, for their help in editing this article and organizing the references.
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Open Access funding enabled and organized by Projekt DEAL. No support was obtained from pharmaceutical companies, in either the conceptualization or preparation of this manuscript.
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Elke Weisshaar is an active member of the European and German guideline group on CHE and co-author of the European and German guidelines on HE. The content of this review reflects her active role in writing texts for these two guidelines. Elke Weisshaar treats HE patients sent by the German (Governmental) Statutory Accident Insurance. She initiated and leads a cohort study on optimized diagnostics of eczema-psoriasis of the hands that is supported by the German (Governmental) Statutory Accident Insurance, and serves as a Vice President and board member of the German Society for Occupational Dermatology (ABD). Elke Weisshaar is also Treasurer of the European Society of Contact Dermatitis; has participated in clinical trials on itch and prurigo for Menlo, Kiniksa, TREVI, and Galderma; and has been a consultant for Galderma, Sanofi, and LEO Pharmaceuticals.
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Weisshaar, E. Chronic Hand Eczema. Am J Clin Dermatol (2024). https://doi.org/10.1007/s40257-024-00890-z
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DOI: https://doi.org/10.1007/s40257-024-00890-z