Interventions for hand eczema
Hand eczema is an inflammation of the skin of the hands that tends to run a chronic, relapsing course. This common condition is often associated with itch, social stigma, and impairment in employment. Many different interventions of unknown effectiveness are used to treat hand eczema.
To assess the effects of topical and systemic interventions for hand eczema in adults and children.
We searched the following up to April 2018: Cochrane Skin Group Specialised Register, CENTRAL, MEDLINE, Embase, AMED, LILACS, GREAT, and four trials registries. We checked the reference lists of included studies for further references to relevant trials.
We included randomised controlled trials (RCTs) that compared interventions for hand eczema, regardless of hand eczema type and other affected sites, versus no treatment, placebo, vehicle, or active treatments.
Data collection and analysis
We used standard methodological procedures expected by Cochrane. Primary outcomes were participant‐ and investigator‐rated good/excellent control of symptoms, and adverse events.
We included 60 RCTs, conducted in secondary care (5469 participants with mild to severe chronic hand eczema). Most participants were over 18 years old. The duration of treatment was short, generally up to four months. Only 24 studies included a follow‐up period. Clinical heterogeneity in treatments and outcome measures was evident. Few studies performed head‐to‐head comparisons of different interventions. Risk of bias varied considerably, with only five studies at low risk in all domains. Twenty‐two studies were industry‐funded.
Eighteen trials studied topical corticosteroids or calcineurin inhibitors; 10 studies, phototherapy; three studies, systemic immunosuppressives; and five studies, oral retinoids. Most studies compared an active intervention against no treatment, variants of the same medication, or placebo (or vehicle). Below, we present results from the main comparisons.
Corticosteroid creams/ointments: when assessed 15 days after the start of treatment, clobetasol propionate 0.05% foam probably improves participant‐rated control of symptoms compared to vehicle (risk ratio (RR) 2.32, 95% confidence interval (CI) 1.38 to 3.91; number needed to treat for an additional beneficial outcome (NNTB) 3, 95% CI 2 to 8; 1 study, 125 participants); the effect of clobetasol compared to vehicle for investigator‐rated improvement is less clear (RR 1.43, 95% CI 0.86 to 2.40). More participants had at least one adverse event with clobetasol (11/62 versus 5/63; RR 2.24, 95% CI 0.82 to 6.06), including application site burning/pruritus. This evidence was rated as moderate certainty.
When assessed 36 weeks after the start of treatment, mometasone furoate cream used thrice weekly may slightly improve investigator‐rated symptom control compared to twice weekly (RR 1.23, 95% CI 0.94 to 1.61; 1 study, 72 participants) after remission is reached. Participant‐rated symptoms were not measured. Some mild atrophy was reported in both groups (RR 1.76, 95% CI 0.45 to 6.83; 5/35 versus 3/37). This evidence was rated as low certainty.
Irradiation with ultraviolet (UV) light: local combination ultraviolet light therapy (PUVA) may lead to improvement in investigator‐rated symptom control when compared to local narrow‐band UVB after 12 weeks of treatment (RR 0.50, 95% CI 0.22 to 1.16; 1 study, 60 participants). However, the 95% CI indicates that PUVA might make little or no difference. Participant‐rated symptoms were not measured. Adverse events (mainly erythema) were reported by 9/30 participants in the narrow‐band UVB group versus none in the PUVA group. This evidence was rated as moderate certainty.
Topical calcineurin inhibitors: tacrolimus 0.1% over two weeks probably improves investigator‐rated symptom control measured after three weeks compared to vehicle (14/14 tacrolimus versus 0/14 vehicle; 1 study). Participant‐rated symptoms were not measured. Four of 14 people in the tacrolimus group versus zero in the vehicle group had well‐tolerated application site burning/itching.
A within‐participant study in 16 participants compared 0.1% tacrolimus to 0.1% mometasone furoate but did not measure investigator‐ or participant‐rated symptoms. Both treatments were well tolerated when assessed at two weeks during four weeks of treatment.
Evidence from these studies was rated as moderate certainty.
Oral interventions: oral cyclosporin 3 mg/kg/d probably slightly improves investigator‐rated (RR 1.88, 95% CI 0.88 to 3.99; 1 study, 34 participants) or participant‐rated (RR 1.25, 95% CI 0.69 to 2.27) control of symptoms compared to topical betamethasone dipropionate 0.05% after six weeks of treatment. The risk of adverse events such as dizziness was similar between groups (up to 36 weeks; RR 1.22, 95% CI 0.80 to 1.86, n = 55; 15/27 betamethasone versus 19/28 cyclosporin). The evidence was rated as moderate certainty.
Alitretinoin 10 mg improves investigator‐rated symptom control compared with placebo (RR 1.58, 95% CI 1.20 to 2.07; NNTB 11, 95% CI 6.3 to 26.5; 2 studies, n = 781) and alitretinoin 30 mg also improves this outcome compared with placebo (RR 2.75, 95% CI 2.20 to 3.43; NNTB 4, 95% CI 3 to 5; 2 studies, n = 1210). Similar results were found for participant‐rated symptom control: alitretinoin 10 mg RR 1.73 (95% CI 1.25 to 2.40) and 30 mg RR 2.75 (95% CI 2.18 to 3.48). Evidence was rated as high certainty. The number of adverse events (including headache) probably did not differ between alitretinoin 10 mg and placebo (RR 1.01, 95% CI 0.66 to 1.55; 1 study, n = 158; moderate‐certainty evidence), but the risk of headache increased with alitretinoin 30 mg (RR 3.43, 95% CI 2.45 to 4.81; 2 studies, n = 1210; high‐certainty evidence). Outcomes were assessed between 48 and 72 weeks.
Most findings were from single studies with low precision, so they should be interpreted with caution. Topical corticosteroids and UV phototherapy were two of the major standard treatments, but evidence is insufficient to support one specific treatment over another. The effect of topical calcineurin inhibitors is not certain. Alitretinoin is more effective than placebo in controlling symptoms, but advantages over other treatments need evaluating.
Well‐designed and well‐reported, long‐term (more than three months), head‐to‐head studies comparing different treatments are needed. Consensus is required regarding the definition of hand eczema and its subtypes, and a standard severity scale should be established.
The main limitation was heterogeneity between studies. Small sample size impacted our ability to detect differences between treatments.
Wietske Andrea Christoffers, Pieter‐Jan Coenraads, Åke Svensson, Thomas L Diepgen, Janine L Dickinson‐Blok, Jun Xia, Hywel C Williams
Plain language summary
Treatments for hand eczema
We reviewed evidence on the effects of topical and systemic (oral or injected medicines that work throughout the entire body) treatments for hand eczema when compared against placebo (an identical but inactive treatment), no treatment, vehicle (inactive ingredients that help deliver an active treatment), or another treatment. We included 60 randomised trials (5469 participants) published up to April 2018.
Hand eczema is an inflammation of the skin of the hands that can be caused by contact allergens (i.e. substances that cause an allergic reaction) such as rubber chemicals, but other external factors (e.g. irritants such as water or detergents) and atopic predisposition are often important triggers. Hand eczema can cause a reduction in quality of life leading to many work‐related problems. Various types of hand eczema exist, and different topical (creams, ointments, or lotions) and systemic treatments with unknown effectiveness can be used.
Most participants were hospital outpatients over 18 years of age with mild to severe chronic hand eczema. Treatment was usually given for up to four months, and outcomes were mainly assessed after treatment. A large variety of treatments were studied and compared to no treatment, variants of the same medication, placebo, or vehicle. Twenty‐two studies were funded by pharmaceutical companies.
Limited data are available to support the best way of managing hand eczema due to varying study quality and inability to pool data from studies with similar interventions. Corticosteroid creams/ointments and phototherapy (irradiation with UV light) are the major treatment options, although comparisons between these options are lacking. Below, we present results for the main comparisons of interest.
Corticosteroid creams/ointments: clobetasol propionate foam probably increases participant‐rated good/excellent control of hand eczema when compared to vehicle (516 versus 222 per 1000), but the difference between groups was less clear for investigator‐rated control, and more adverse events were reported with clobetasol propionate (178 versus 79 per 1000) (all based on moderate‐certainty evidence).
Mometasone furoate cream used thrice weekly may slightly improve investigator‐rated good/excellent control compared to twice weekly treatment, and participant‐rated control was not measured. Mild skin thinning occurred in both groups, but cases were few (all based on low‐certainty evidence).
Irradiation with UV light: various types of irradiation (i.e. exposure to radiation) were compared. Local PUVA may improve investigator‐rated good/excellent control compared to narrow‐band UVB (400 versus 200 per 1000); however, we are uncertain of this finding because results also show that local PUVA may make little or no difference. Participant‐rated symptoms were not measured. Nine out of 30 participants in the narrow‐band UVB group reported adverse events (mainly redness) compared to none in the PUVA group (all based on moderate‐certainty evidence).
Topical calcineurin inhibitors: people receiving tacrolimus are probably more likely to achieve improved investigator‐rated good/excellent symptom control compared to those given vehicle (14/14 participants with tacrolimus compared to none with vehicle), but participant‐rated control of symptoms was not measured. Four of 14 people in the tacrolimus group versus zero in the vehicle group had well‐tolerated application site burning/itching. One small study compared tacrolimus to mometasone furoate, which were both well tolerated, but did not measure investigator‐ or participant‐rated control (all based on moderate‐certainty evidence).
Oral interventions: oral immunosuppressant (a drug that hinders the immune response) cyclosporin probably slightly improves investigator‐ or participant‐rated control of good/excellent symptoms compared to topical betamethasone cream (a corticosteroid). The risk of adverse events such as dizziness was similar between groups (all based on moderate‐certainty evidence).
The oral vitamin A derivative (retinoid) alitretinoin (10 mg) achieved investigator‐rated good/excellent symptom control in 307 compared to 194 participants per 1000 with placebo, and alitretinoin 30 mg achieved investigator‐rated control in 432 compared to 157 participants per 1000 with placebo. Similar results were shown for participant‐rated control (high‐certainty evidence). When the dosage of alitretinoin was increased to 30 mg, risk of headache was higher compared to placebo (74 versus 251 per 1000; high‐certainty evidence), but this probably does not differ between alitretinoin 10 mg and placebo (based on moderate‐certainty evidence).
Quality of the evidence
The quality of evidence was mainly moderate, with most analyses based on single studies that had small sample sizes; therefore, some results should be interpreted with care.
Wietske Andrea Christoffers, Pieter‐Jan Coenraads, Åke Svensson, Thomas L Diepgen, Janine L Dickinson‐Blok, Jun Xia, Hywel C Williams
Implications for practice
The results of this review cannot be used to inform clinical practice with regard to the best way of managing hand eczema, especially in the long term. Until such data are forthcoming, physicians will be tempted to use an array of treatments.
For the comparison of clobetasol propionate versus vehicle foam, the percentage of participants with self‐rated good/excellent control of symptoms probably improves with clobetasol propionate, but the effect is less clear for investigator‐rated symptoms (moderate‐quality evidence). Mometasone furoate cream thrice weekly may slightly improve investigator‐rated symptoms compared to twice weekly application (low‐quality evidence); participant‐rated control was not measured.
Tacrolimus ointment probably improves investigator‐rated good/excellent control of symptoms compared to vehicle foam (moderate‐quality evidence); participant‐rated control was not measured.
A relatively new systemic treatment (an oral retinoid called alitretinoin) for patients with severe chronic hand eczema showed clearance or almost clearance of about half the participants in three large RCTs (Fowler 2014; Ruzicka 2004, Ruzicka 2008). We found high‐quality evidence that relative to placebo, people who are given alitretinoin were more likely to achieve good symptom control (investigator or participant rated). The benefit became more apparent with increased dosage (10 mg versus 30 mg).
Local PUVA may lead to improvement compared to local narrow‐band UVB; however, the 95% confidence interval indicates that local PUVA might make little or no difference (moderate‐quality evidence). Participant‐rated control was not measured.
Oral cyclosporin probably slightly improves investigator‐/participant‐rated control of symptoms compared with topical betamethasone dipropionate (moderate‐quality evidence).
For the comparison tacrolimus 0.1% ointment versus mometasone furoate ointment, investigator‐rated symptoms and participant‐rated control was not measured.
Adverse events: adverse (long‐ and short‐term) effects of the interventions
- Clobetasol propionate led to more adverse events (including application site burning/pruritus after intervention application, nasopharyngitis, and one incident of severe fissures) compared to vehicle foam (moderate‐quality evidence)
- With regard to mometasone furoate cream used thrice weekly compared to twice weekly, mild atrophy was reported in both groups (low‐quality evidence)
- When compared to local PUVA, adverse events (mainly erythema) were reported in the local narrow‐band UVB group only (moderate‐quality evidence)
- With regard to tacrolimus ointment compared to mometasone furoate ointment, both treatments were well tolerated; none of the participants dropped out due to adverse events (moderate‐quality evidence)
- When compared to vehicle foam, adverse events (well‐tolerated burning/itching at the application site) were reported in the group taking tacrolimus ointment only (moderate‐quality evidence)
- The risk of adverse events such as dizziness was fairly similar between those taking oral cyclosporin and those taking topical betamethasone dipropionate (moderate‐quality evidence)
The 20 studies listed under Studies awaiting classification may alter the conclusions of the review once assessed.
Implications for research
The most important implication of this review is the need to conduct high‐quality RCTs of people with hand eczema to compare commonly used interventions by using simple outcome measures that can be understood by participants and clinicians.
- E (Evidence): current evidence for managing hand eczema is mainly of low to moderate certainty and especially head‐to‐head trials are missing. Recently, head‐to‐head trials for different (systemic) treatments have been registered in trial registries (ISRCTN80206075; NCT03026907; NCT03026946), which might alter the outcomes of this review in the near future.
- P (Population): people with chronic (longer than six months) moderate to severe hand eczema should be included in future trials. Subgroup analyses on participants with different variants of hand eczema are recommended, although lack of consensus regarding the classification of hand eczema is a major limitation. We need international consensus regarding the definition of (chronic) hand eczema and subgroups of hand eczema, based on morphology or aetiology. Subgroups of especial interest include participants with hyperkeratotic hand eczema and participants with recurrent vesicular hand eczema. Studies on acute hand eczema were not included in this review but may be of interest, especially in primary care settings. Not many children were included in these studies, and this is a potential subgroup of interest for future studies.
- I (Intervention): all sources of treatment can be included, although we would recommend including the main interventions (topical corticosteroids, UV therapy, topical calcineurin inhibitors, acitretin, alitretinoin, and cyclosporin).
- C (Comparison): head‐to‐head trials, in which different groups of commonly used interventions are compared, are highly desirable, for example, cyclosporin versus alitretinoin or UVA therapy versus topical corticosteroids. If an RCT includes placebo (or vehicle or inactive treatment) as the only comparator instead of an established treatment modality, this should be clearly and convincingly justified.
- O (Outcome): at the moment, international consensus on a standard severity scale for hand eczema is lacking. Many of the scales used were not validated, and validation of commonly used scoring systems is needed. Alternatively, a simple global rating measure with, for example, photographic anchors is highly recommended (Charman 2005; Weistenhöfer 2010). We would like to recommend the same procedure as is currently ongoing in atopic dermatitis: Harmonising Outcome Measures for Eczema (HOME) (Schmitt 2010). The HOME group is a worldwide initiative with the aim of developing a consensus‐based set of core outcome domains for trials and clinical record keeping in atopic dermatitis. This is important, to allow comparison of data across trials ‐ one of the difficulties that we encountered in this review on interventions for hand eczema. Duration of remission, the way the disease is brought under control, adverse events, focus on patient‐reported outcomes, and simple outcome measures applicable to all participants are preferable. Hand eczema is known to influence quality of life; therefore quality of life should be an important outcome. In addition, trials should focus on economic consequences, since hand eczema is a common occupational disease. A major limitation of almost all reviewed trials is that no measure of effect size including precision is given. This is necessary to enable judgement of whether advantages of treatments are not only statistically significant but also meaningful.
- T (Time stamp): our latest search was conducted in April 2018. Older studies focused mainly on topical corticosteroids, UV therapy, and irradiation, and more recent (namely, industry‐funded) studies focus on topical calcineurin inhibitors (pimecrolimus and tacrolimus) and alitretinoin. The included studies were predominantly of short duration. Future studies should have adequate treatment duration, preferably longer than three months, which in our opinion is the minimum duration required to document important data such as duration and frequency of disease relapse. Furthermore, studies on chronic hand eczema should include a follow‐up period of at least equal duration. Acute hand eczema, especially the allergic type, tends to respond quickly to treatment and needs only a short follow‐up, in which case a few weeks of treatment and follow‐up should be sufficient.
It is obvious in many of the reviewed trials that the approach to statistical analyses was limited. Several parametric and non‐parametric statistical procedures that are able to model both within (person and/or time) and between subject (treatment) factors simultaneously have been offered by most statistical packages for many years. A major limitation of many of the treatment comparisons is that they did not control for baseline variation. In addition, omnibus factorial designs (allowing contrasts to be specified a priori) reduce the type 1 error rate because they test several hypotheses at the same time. Post‐hoc comparisons would be necessary only should the data reveal surprising results. These analyses, of course, would have to be viewed in an explorative fashion. Future studies need to overcome said limitations.
Many deficiencies in trial reporting thus far can be avoided if all specialist dermatology journals adopt the CONSORT guidelines (Moher 2001), especially since many of the 'unclear' risks, turned out to be based on missing information in the report instead of flaws in the study design. All future studies should adhere to these guidelines. Future studies should ensure they are adequately powered to detect any differences between treatment groups and to reduce imprecision.
Practical recommendations for upcoming studies include the above‐mentioned recommendations on chronic hand eczema. Studies that are highly recommended include the comparison of phototherapy (e.g. bath‐PUVA) versus alitretinoin 30 mg in a large cohort of participants with chronic hand eczema with a duration of at least three months and follow‐up of at least equal length. This study is already registered (ISRCTN80206075), and results of this trial might influence the outcomes of this review in future updates.
Another recommendation would be to compare alitretinoin 30 mg to cyclosporin in participants with vesicular hand eczema and with hyperkeratotic hand eczema, since participants with vesicular hand eczema seemed to respond less to alitretinoin in the included trials on alitretinoin. This study design is already registered for vesicular hand eczema as well, and we are awaiting the results (NCT03026946). Other potential research options include comparison of a potent topical corticosteroid, since this is the mainstream of treatment, to alitretinoin 30 mg or to phototherapy. The comparative advantage over other treatments needs further evaluation, since the only study that did compare alitretinoin to another immunosuppressant (cyclosporin) was ended prematurely (NCT01231854).