Phototherapy for atopic eczema Edited (no change to conclusions)

Abstract

Background

Atopic eczema (AE), also known as atopic dermatitis, is a chronic inflammatory skin condition that causes significant burden. Phototherapy is sometimes used to treat AE when topical treatments, such as corticosteroids, are insufficient or poorly tolerated.

Objectives

To assess the effects of phototherapy for treating AE.

Search methods

We searched the Cochrane Skin Specialised Register, CENTRAL, MEDLINE, Embase, and ClinicalTrials.gov to January 2021.

Selection criteria

We included randomised controlled trials in adults or children with any subtype or severity of clinically diagnosed AE. Eligible comparisons were any type of phototherapy versus other forms of phototherapy or any other treatment, including placebo or no treatment.

Data collection and analysis

We used standard Cochrane methodology. For key findings, we used RoB 2.0 to assess bias, and GRADE to assess certainty of the evidence. Primary outcomes were physician‐assessed signs and patient‐reported symptoms. Secondary outcomes were Investigator Global Assessment (IGA), health‐related quality of life (HRQoL), safety (measured as withdrawals due to adverse events), and long‐term control.

Main results

We included 32 trials with 1219 randomised participants, aged 5 to 83 years (mean: 28 years), with an equal number of males and females. Participants were recruited mainly from secondary care dermatology clinics, and study duration was, on average, 13 weeks (range: 10 days to one year). We assessed risk of bias for all key outcomes as having some concerns or high risk, due to missing data, inappropriate analysis, or insufficient information to assess selective reporting.

Assessed interventions included: narrowband ultraviolet B (NB‐UVB; 13 trials), ultraviolet A1 (UVA1; 6 trials), broadband ultraviolet B (BB‐UVB; 5 trials), ultraviolet AB (UVAB; 2 trials), psoralen plus ultraviolet A (PUVA; 2 trials), ultraviolet A (UVA; 1 trial), unspecified ultraviolet B (UVB; 1 trial), full spectrum light (1 trial), Saalmann selective ultraviolet phototherapy (SUP) cabin (1 trial), saltwater bath plus UVB (balneophototherapy; 1 trial), and excimer laser (1 trial). Comparators included placebo, no treatment, another phototherapy, topical treatment, or alternative doses of the same treatment.

Results for key comparisons are summarised (for scales, lower scores are better):

NB‐UVB versus placebo/no treatment 

There may be a larger reduction in physician‐assessed signs with NB‐UVB compared to placebo after 12 weeks of treatment (mean difference (MD) ‐9.4, 95% confidence interval (CI) ‐3.62 to ‐15.18; 1 trial, 41 participants; scale: 0 to 90). Two trials reported little difference between NB‐UVB and no treatment (37 participants, four to six weeks of treatment); another reported improved signs with NB‐UVB versus no treatment (11 participants, nine weeks of treatment).

NB‐UVB may increase the number of people reporting reduced itch after 12 weeks of treatment compared to placebo (risk ratio (RR) 1.72, 95% CI 1.10 to 2.69; 1 trial, 40 participants). Another trial reported very little difference in itch severity with NB‐UVB (25 participants, four weeks of treatment).

The number of participants with moderate to greater global improvement may be higher with NB‐UVB than placebo after 12 weeks of treatment (RR 2.81, 95% CI 1.10 to 7.17; 1 trial, 41 participants).

NB‐UVB may not affect rates of withdrawal due to adverse events. No withdrawals were reported in one trial of NB‐UVB versus placebo (18 participants, nine weeks of treatment). In two trials of NB‐UVB versus no treatment, each reported one withdrawal per group (71 participants, 8 to 12 weeks of treatment).

We judged that all reported outcomes were supported with low‐certainty evidence, due to risk of bias and imprecision. No trials reported HRQoL.

NB‐UVB versus UVA1 

We judged the evidence for NB‐UVB compared to UVA1 to be very low certainty for all outcomes, due to risk of bias and imprecision. There was no evidence of a difference in physician‐assessed signs after six weeks (MD ‐2.00, 95% CI ‐8.41 to 4.41; 1 trial, 46 participants; scale: 0 to 108), or patient‐reported itch after six weeks (MD 0.3, 95% CI ‐1.07 to 1.67; 1 trial, 46 participants; scale: 0 to 10). Two split‐body trials (20 participants, 40 sides) also measured these outcomes, using different scales at seven to eight weeks; they reported lower scores with NB‐UVB. One trial reported HRQoL at six weeks (MD 2.9, 95% CI ‐9.57 to 15.37; 1 trial, 46 participants; scale: 30 to 150). One split‐body trial reported no withdrawals due to adverse events over 12 weeks (13 participants). No trials reported IGA.

NB‐UVB versus PUVA 

We judged the evidence for NB‐UVB compared to PUVA (8‐methoxypsoralen in bath plus UVA) to be very low certainty for all reported outcomes, due to risk of bias and imprecision. There was no evidence of a difference in physician‐assessed signs after six weeks (64.1% reduction with NB‐UVB versus 65.7% reduction with PUVA; 1 trial, 10 participants, 20 sides). There was no evidence of a difference in marked improvement or complete remission after six weeks (odds ratio (OR) 1.00, 95% CI 0.13 to 7.89; 1 trial, 9/10 participants with both treatments). One split‐body trial reported no withdrawals due to adverse events in 10 participants over six weeks. The trials did not report patient‐reported symptoms or HRQoL.

UVA1 versus PUVA 

There was very low‐certainty evidence, due to serious risk of bias and imprecision, that PUVA (oral 5‐methoxypsoralen plus UVA) reduced physician‐assessed signs more than UVA1 after three weeks (MD 11.3, 95% CI ‐0.21 to 22.81; 1 trial, 40 participants; scale: 0 to 103). The trial did not report patient‐reported symptoms, IGA, HRQoL, or withdrawals due to adverse events.

There were no eligible trials for the key comparisons of UVA1 or PUVA compared with no treatment.

Adverse events 

Reported adverse events included low rates of phototoxic reaction, severe irritation, UV burn, bacterial superinfection, disease exacerbation, and eczema herpeticum.

Authors' conclusions

Compared to placebo or no treatment, NB‐UVB may improve physician‐rated signs, patient‐reported symptoms, and IGA after 12 weeks, without a difference in withdrawal due to adverse events. Evidence for UVA1 compared to NB‐UVB or PUVA, and NB‐UVB compared to PUVA was very low certainty. More information is needed on the safety and effectiveness of all aspects of phototherapy for treating AE.

Author(s)

Annelie H Musters, Soudeh Mashayekhi, Jane Harvey, Emma Axon, Stephanie J Lax, Carsten Flohr, Aaron M Drucker, Louise Gerbens, John Ferguson, Sally Ibbotson, Robert S Dawe, Floor Garritsen, Marijke Brouwer, Jacqueline Limpens, Laura E Prescott, Robert J Boyle, Phyllis I Spuls

Abstract

Plain language summary

What are the benefits and risks of light therapy for treating atopic eczema (also known as eczema or atopic dermatitis)? 

Key messages 

Narrowband (NB) ultraviolet B (UVB), compared to placebo (a sham treatment), may improve eczema severity (including itch) and may not affect the number of people leaving a study because of unwanted effects.

We were unable to confidently draw conclusions for other phototherapy (light therapy) treatments.

Future research needs to assess longer term effectiveness and safety of NB‐UVB and other forms of phototherapy for eczema.

What is eczema? 

Eczema is a condition that results in dry, itchy patches of inflamed skin. Eczema typically starts in childhood, but can improve with age. Eczema is caused by a combination of genetics and environmental factors, which lead to skin barrier dysfunction. Eczema can negatively impact quality of life, and the societal cost is significant.

How is eczema treated? 

Eczema treatments are often creams or ointments that reduce itch and redness, applied directly to the skin. If these are unsuccessful, systemic medicines that affect the whole body, or phototherapy are options. Phototherapy can be UVB, ultraviolet A (UVA), or photochemotherapy (PUVA), where phototherapy is given alongside substances that increase sensitivity to UV light.

What did we want to find out? 

We wanted to find out whether phototherapy was better than no treatment or other types of treatment for treating eczema, and whether it caused unwanted effects.

What did we do? 

We searched for studies that investigated phototherapy compared with no treatment, placebo, other forms of phototherapy, or another type of eczema treatment. Studies could include people of all ages, who had eczema diagnosed by a healthcare professional.

We compared and summarised the results of the studies, and rated our confidence in the evidence.

What did we find? 

We found 32 studies, involving 1219 people with eczema (average age: 28 years), who were recruited from dermatology clinics. Most studies assessed people with skin type II to III (which is classed as white to medium skin colour), and moderate to severe eczema, with which they had lived for many years. Studies included similar numbers of males and females.

The studies were conducted in Europe, Asia, and Egypt (setting was not reported by seven studies), and lasted, on average, for 13 weeks. Almost half of the studies reported their source of funding; two were linked to commercial sponsors.

Our included studies mostly assessed NB‐UVB, followed by UVA1, then broadband ultraviolet B; fewer studies investigated other types of phototherapy. The studies compared these treatments to placebo, or no treatment, another type of phototherapy, different doses of the same sort of phototherapy, or other eczema treatments applied to the skin or taken by tablet.

None of the studies investigated excimer lamp (a source of UV radiation) or heliotherapy (the use of natural sunlight), that were other light therapies in which we were interested.

What are the main results of our review? 

When compared to placebo, NB‐UVB may:

‐ improve signs of eczema assessed by a healthcare professional (1 study, 41 people);

‐ increase the number of people reporting less severe itching (1 study, 41 people);

‐ increase the  number of people reporting moderate or greater improvement of eczema, measured by the Investigator Global Assessment scale (IGA), a 5‐point scale that measures improvement in eczema symptoms (1 study, 40 people); and

‐ have no effect on the rate of people withdrawing from treatment due to unwanted effects (3 studies, 89 people).

None of the studies assessing NB‐UVB against placebo measured health‐related quality of life.

We do not know if NB‐UVB (compared with UVA1 or PUVA) or UVA1 (compared with PUVA) has an effect on the following:

‐ signs of eczema assessed by a healthcare professional;

‐ patient‐reported eczema symptoms;

‐ IGA;

‐ health‐related quality of life; and

‐ withdrawals due to unwanted effects.

This is because either we are not confident in the evidence, or they were not reported.

We did not identify any studies that investigated UVA1 or PUVA compared with no treatment.

Some studies reported that phototherapy caused some unwanted effects, including skin reactions or irritation, UV burn, worsening of eczema, and skin infections. However, these did not occur in most people.

What are the limitations of the evidence? 

Our confidence in the evidence is limited, mainly because only a few studies could be included in each comparison, and the studies generally involved only small numbers of people.

How up to date is this evidence? 

The evidence is up to date to January 2021.

Author(s)

Annelie H Musters, Soudeh Mashayekhi, Jane Harvey, Emma Axon, Stephanie J Lax, Carsten Flohr, Aaron M Drucker, Louise Gerbens, John Ferguson, Sally Ibbotson, Robert S Dawe, Floor Garritsen, Marijke Brouwer, Jacqueline Limpens, Laura E Prescott, Robert J Boyle, Phyllis I Spuls

Reviewer's Conclusions

Authors' conclusions 

Implications for practice 

We found little evidence for our key comparisons, each of which were assessed by a range of only one to four studies that we were often unable to pool. Furthermore, our key results were based on very low‐ to low‐certainty evidence. This means we cannot draw firm conclusions about the effectiveness and safety of phototherapy for atopic eczema. 

Reported adverse events associated with phototherapy included phototoxic reaction, severe irritation, ultraviolet‐induced erythema, bacterial superinfection, exacerbation of disease, and eczema herpeticum. However, rates of occurrence were low, and did not differ between different phototherapy modalities.

However, lack of high quality RCT evidence does not mean lack of effectiveness of these treatments. Besides, the included studies did not provide the data needed to determine how the interventions differ according to age, Fitzpatrick skin type, AE phenotype, or HIV/AIDS co‐morbidity, which limits external validity. The studies assessed our outcomes in the short‐term (less than 16 weeks), which does not align with AE as a long‐term condition. The vast majority of studies did not report long‐term control or duration on remission after the phototherapy treatment course has ended. 

We found no studies assessing coal tar plus UVB radiation (Goeckerman therapy), oral trimethylpsoralen with UVA, oral or topical khellin in combination with UV, heliotherapy and excimer lamp. Only two trials investigated PUVA, so there is a lack of evidence to assess this treatment, while it's frequently prescribed in Europe (Vermeulen 2020). Studies in psoriasis showed that there are indications for an increased incidence of actinic keratoses and skin malignancies after systemic PUVA treatment and a positive correlation is seen with the cumulative UVA dose/number of PUVA exposures (Archier 2012; Stern 1998; Henseler 1987; Stern 1994). A Swedish study assessing the risk of skin malignancies in people with AE treated with PUVA did not find any increased risk for melanoma, but confirmed previous reports of an increased incidence of cutaneous squamous cell carcinoma (Lindelöf 1991; Lindelöf 1999). This information should be taken into account when prescribing PUVA.

Our primary outcome physician‐assessed changes in clinical signs was reported by almost all studies (compared to patient‐reported changes in symptoms, which was assessed by just less than half); however, the tools used to measure these outcomes were not HOME core instruments and were very heterogeneous. Safety data related to withdrawals were limited.

Implications for research 

Currently, only very low‐ to low‐certainty evidence is available on the efficacy of narrowband ultraviolet B (NB‐UVB) versus no treatment or placebo, NB‐UVB versus UVA1, and PUVA versus UVA1 or NB‐UVB. We found no studies evaluating the other main comparisons of our review (UVA1 versus no treatment or placebo and psoralenUVA (PUVA) versus no treatment or placebo), so future studies are needed to assess these and our other main comparisons, focusing on NB‐UVB, UVA1, and PUVA. Information on duration of remission and long‐term efficacy and safety (especially skin cancer risk) of phototherapy for atopic eczema is scarce, and more research is needed to investigate these outcomes. Collecting data on (long‐term) safety of combinations of phototherapy with other systemic or topical treatments (e.g. tacrolimus) or certain treatment sequences (e.g. phototherapy after systemic immunomodulating treatment) would also be of interest, as people with moderate to severe atopic eczema receive numerous treatment modalities and sequences.

Studies evaluating the efficacy of phototherapy for atopic eczema use a wide variation of outcome measurements and study parameters. Future studies should use outcome measures that reflect the core outcomes (including core outcome instruments) of the Harmonising Outcome Measures for Eczema (HOME) initiative in order to compare and pool data.  As we found that previous studies evaluating the efficacy of phototherapy in atopic eczema reported very little data on (skin specific) quality of life and other self‐reported outcomes, these outcomes should be assessed in future studies.

Trials used different methods for participant selection (including atopic eczema diagnosis), phototherapy dosing regimens, and administration. Future studies should include participants who were diagnosed with atopic eczema using validated criteria, and longer follow‐up periods (≥ six months). More homogeneous study designs, with standardised treatment procedures and cumulative doses should also be used, so that they can be pooled in future systematic reviews. Researchers investigating the effectiveness of phototherapy in trials in which participants are treated with concomitant topical corticosteroids are advised to keep track of the amount of topicals that are used.

Correctly designed randomised controlled trials (RCT) should be used to evaluate the effectiveness and safety of phototherapy for atopic eczema in the future, as insufficient reporting of study methodology may lead to biased assessment of treatment effects (Schulz 1995). Future RCTs should include power calculations to establish that adequate participant numbers are included. We recommend that investigators of future (parallel‐group) RCTs assessing the effectiveness and safety of phototherapy for atopic eczema consult the CONSORT statement (Schulz 2010).

Data on the effectiveness and safety of phototherapy in certain populations, such as children or people with particular skin types are lacking, and should be considered for future research. We emphasise the need of future studies to investigate the effectiveness and safety of phototherapy in people with skin of colour. Phototherapy for acute versus chronic atopic eczema and other phenotypes should be further investigated. Home phototherapy should also be considered in future studies.

In addition to the results of this systematic review evaluating the existing evidence on phototherapy assessed through RCTs, cohort data of clinical daily practice could be useful. Real‐world data on the (long‐term) efficacy of phototherapy, for example from the European TREatment of ATopic eczema (TREAT) Registry Taskforce, could be beneficial to develop recommendations and inform clinical guidelines.

As the costs of atopic eczema per person are rising, due to the introduction of new systemic treatments, such as monoclonal antibodies and Janus kinase (JAK) inhibitors, high‐quality research into the effectiveness, safety, and cost‐effectiveness of skin‐directed alternatives, like phototherapy, is of great importance.

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